Doxorubicin(DOX)is known to elicit potent antitumor immune responses through the induction of immunogenic cell death(ICD).However,its therapeutic efficacy is undermined by the adaptive upregulation of programmed cell ...Doxorubicin(DOX)is known to elicit potent antitumor immune responses through the induction of immunogenic cell death(ICD).However,its therapeutic efficacy is undermined by the adaptive upregulation of programmed cell death ligand 1(PD-L1),which hijacked the antitumor immunity.In this study,we developed a reactive oxygen species(ROS)-responsive dihydroartemisinin(DHA)prodrug to facilitate the delivery of DOX via hydrophobic and electrostatic interactions.Upon internalization by tumor cells,the nanoparticles(NPs)preferentially accumulated in endoplasmic reticulum(ER),exacerbating ER stress and amplifying ICD to enhance tumor immunogenicity.Simultaneously,the oxidative intracellular environment trigged the degradation of NPs,releasing DHA,which downregulated PD-L1 by disrupting signal transducer and activator of transcription 3(STAT3)phosphorylation and inactivating the nuclear factor kappa-B(NF-κB)pathway.Consequently,the effective PD-L1 blockade and robust ICD response,synergistically inhibited breast cancer progression,significantly enhancing the chemo-immunotherapy efficacy of doxorubicin.展开更多
Dysfunction of anti-tumor immune responses is crucial for cancer progression. Immune checkpoint blockade(ICB), which can potentiate T cell responses, is an effective strategy for the normalization of host anti-tumor i...Dysfunction of anti-tumor immune responses is crucial for cancer progression. Immune checkpoint blockade(ICB), which can potentiate T cell responses, is an effective strategy for the normalization of host anti-tumor immunity. In recent years, immune checkpoints, expressed on both tumor cells and immune cells, have been identified;some of them have exhibited potential druggability and have been approved by the US Food and Drug Administration(FDA) for clinical treatment. However, limited responses and immune-related adverse events(ir AEs) cannot be ignored. This review outlines the development and applications of ICBs, potential strategies for overcoming resistance, and future directions for ICB-based cancer immunotherapy.展开更多
Objective:To investigate the anti-tumor effects of an E1B55KD-deleted oncolytic adenovirus,H101,in combination with a humanized anti-PD-1(Programmed cell death protein 1)monoclonal antibody,Camrelizumab.Methods:Anti-t...Objective:To investigate the anti-tumor effects of an E1B55KD-deleted oncolytic adenovirus,H101,in combination with a humanized anti-PD-1(Programmed cell death protein 1)monoclonal antibody,Camrelizumab.Methods:Anti-tumor efficacy of intratumoral injection of H101 or/and intraperitoneal injection of Camrelizumab were evaluated in an immune system humanized NOD Prkdc^(scid) Il2rg^(-/-)mice subcutaneous(S.C.)tumor model,established with human glioblastoma of unknown origin cell line U87-MG,and human bladder cancer cell line T24 and YTS-1.The mechanism by which H101 induced anti-tumor immunity were also investigated.Results:Combining H101 with Camrelizumab demonstrated more potent anti-tumor effects than monotherapy in mouse S.C.tumor model.Increased tumor-infiltrating T cells were observed in the combined treatment group.H101 infection decreased the expression of CD47 in cancer cells,thereby promoting macrophages to phagocytose cancer cells.Following the H101-mediated activation of macrophages,increased levels of cytokines,including TNF,IL-12 and IFN-γwere observed.Moreover,when induced THP-1 cells were co-cultured with H101-treated cancer cells,expression of IFN-γwas increased in T cells.Elimination of IL-12 using an anti-IL-12 antibody abolished IFN-γproduction from T cells.In addition,infection with H101 increased PD-L1 expression in YTS-1 cells.These results suggested that H101 may act synergistically to enhance the therapeutic efficacy of PD-1 blockade in cancer via suppressing CD47 signaling,which may promote macrophages to phagocytose tumor cells and activate CD8^(+)T cells.Conclusion:The combination of H101 with PD-1 blockade exhibits potential as a novel strategy for the treatment of cancer.展开更多
BACKGROUND Bradycardia,renal failure,atrioventricular nodal blockade,shock,and hyper-kalemia(BRASH)syndrome is an acronym used to describe a constellation of BRASH.It is an underrecognized phenomenon that can be deadl...BACKGROUND Bradycardia,renal failure,atrioventricular nodal blockade,shock,and hyper-kalemia(BRASH)syndrome is an acronym used to describe a constellation of BRASH.It is an underrecognized phenomenon that can be deadly if not appro-priately managed in a timely manner.This case highlights the importance of rapid diagnosis and reviews a multitude of treatment options in a uniquely severe case of BRASH syndrome.CASE SUMMARY We present a case of a 54-year-old male on a beta-blocker and angiotensin-con-verting enzyme inhibitor who presented with one day history of nausea,vomi-ting,and shortness of breath.Upon presentation,he was bradycardic and hypotensive,requiring transcutaneous pacing.Initial electrocardiogram showed atrial fibrillation with ventricular rate in 30’s.He was found to have acute kidney injury,hyperkalemia,and metabolic acidosis.He was successfully treated with multiple potassium lowering agents,continuous renal replacement therapy,four pressors,mechanical ventilation,and transvenous pacing with complete recovery prior to discharge.CONCLUSION Increased awareness of BRASH syndrome may improve outcomes through timely diagnosis and aggressive intervention.展开更多
Therapeutic antibodies of targeting the programmed cell death protein 1(PD-1)/programmed death-ligand 1(PD-L1)pathway are used in hepatocellular carcinoma(HCC)treatment,but are limited by low response rates and immune...Therapeutic antibodies of targeting the programmed cell death protein 1(PD-1)/programmed death-ligand 1(PD-L1)pathway are used in hepatocellular carcinoma(HCC)treatment,but are limited by low response rates and immune-related toxicity[1].Searching for treatment approaches to combine with PD-1/PD-L1 blockade may potentially enhance the efficacy of PD-1/PD-L1 blockade and reduce its side effects.展开更多
Tumor blockade therapy inhibits tumor progression by cutting off essential supplies of nutrients,oxygen,and biomolecules from the surrounding microenvironments.Inspired by natural processes,tumor biomineralization has...Tumor blockade therapy inhibits tumor progression by cutting off essential supplies of nutrients,oxygen,and biomolecules from the surrounding microenvironments.Inspired by natural processes,tumor biomineralization has evolved due to its biocompatibility,self-reinforcing capability,and penetrationindependent mechanism.However,the selective induction of tumor biomineralization using synthetic tools presents a significant challenge.Herein,a metabolic glycoengineering-assistant tumor biomineralization strategy was developed.Specifically,the azido group(N_(3))was introduced onto the cytomembrane by incubating tumor cells with glycose analog Ac4ManNAz.In addition,a bisphosphonate-containing polymer,dibenzocyclooctyne-poly(ethylene glycol)-alendronate(DBCO-PEG-ALN,DBPA)was synthesized,which attached to the tumor cell surface via"click chemistry"reaction between DBCO and N_(3).Subsequently,the bisphosphonate group on the cell surface chelated with positively charged ions in the microenvironments,triggering a consecutive process of biomineralization.This physical barrier significantly reduced tumor cell viability and mobility in a calcium ion concentration-dependent manner,suggesting its potential as an effective anti-tumor strategy for in vivo applications.展开更多
Mitochondria provides adenosine triphosphate for multiple vital movements to ensure tumor cell proliferation.Compared to the broadly used method of inducing DNA replication arrest to kill cancer,inducing mitochondria ...Mitochondria provides adenosine triphosphate for multiple vital movements to ensure tumor cell proliferation.Compared to the broadly used method of inducing DNA replication arrest to kill cancer,inducing mitochondria damage to cause energy shortage is quite promising as it can inhibit tumor cell bioactivities,increase intracellular accumulation of toxic drugs,eventually sensitize chemotherapy and even reverse drug resistance.Breaking the balance of glutathione(GSH)and reactive oxygen species(ROS)contents have been proven efficient in destroying mitochondria respectively.Herein,apigenin,a GSH efflux reagent,and 2-deoxy-5-fluorouridine 5-monophosphate sodium salt(FdUMP)that could induce toxic ROS were co-delivered by constructed lipid nanoparticles,noted as Lip@AF.An immune-checkpoint inhibition reagent CD276 antibody was modified onto the surface of Lip@AF with high reaction specificity(noted asαCD276-Lip@AF)to enhance the recognition of immune cells to tumor.Results showed that the redox balancewas destroyed,leading to severe injury to mitochondria and cell membrane.Furthermore,synergistic DNA/RNA replication inhibition caused by inhibiting the function of thymidylate synthase were observed.Eventually,significantly enhanced cytotoxicity was achieved by combining multiple mechanisms including ferroptosis,apoptosis and pyroptosis.In vivo,strengthen tumor growth inhibitionwas achieved byαCD276-Lip@AF with high biosafety,providing new sights in enhancing chemotherapy sensitiveness and achieving high-performance chemo-immunotherapy.展开更多
BACKGROUND Irreversible electroporation(IRE)represents an innovative localized technique for tumor ablation,possessing the capacity to activate the immune response of the host.However,this method alone is inadequate t...BACKGROUND Irreversible electroporation(IRE)represents an innovative localized technique for tumor ablation,possessing the capacity to activate the immune response of the host.However,this method alone is inadequate to halt cancer progression,necessitating the integration of additional strategies to achieve effective immuno-therapy.AIM To investigate the effects and underlying mechanisms of antitumor immunity derived from the synergistic application of IRE and anti-programmed cell death protein 1(PD-1)therapy within a murine model of hepatocellular carcinoma.METHODS C57BL-6 mice with tumor growth were divided into four separate cohorts:Control group;IRE group;Anti-PD-1 group;And IRE+anti-PD-1 group.The infiltration levels of T,B,and natural killer cells within the tumors,as well as the plasma concentrations of T helper type 1 cytokines(interleukin-2,interferon-γ,and tumor necrosis factor-β),were evaluated.Real-time polymerase chain reaction was utilized to quantify the expression of cluster of differentiation(CD)8(a marker indicative of CD8+T cells)in the tumor specimens of the mice at various temporal intervals.Tumor growth trajectories were charted.RESULTS The results indicated that the IRE+anti-PD-1 group exhibited significantly heightened percentages of T lymphocyte infiltration,particularly CD4+and CD8+T cells,when compared to the control cohort.Additionally,this group displayed increased infiltration of natural killer and B cells,augmented cytokine levels,and elevated CD8 messenger RNA expression.A marked decrease in tumor volume was noted in the IRE+anti-PD-1 group,indicating enhanced therapeutic efficacy.CONCLUSION The combined application of IRE and checkpoint blockade elicits an antitumor immune response,leading to a more substantial reduction in tumor volume and improved therapeutic outcomes,thereby establishing a novel avenue for the ablation and immunotherapy of hepatocellular carcinoma.展开更多
The circuit quantum electrodynamics(QED)system has brought us into an ultrastrong and deep coupling regime in the light-matter interaction community,in which the quantum effect has attracted significant interest.In th...The circuit quantum electrodynamics(QED)system has brought us into an ultrastrong and deep coupling regime in the light-matter interaction community,in which the quantum effect has attracted significant interest.In this study,we theoretically investigated the photon blockade phenomenon in a double-transmon system operating in an ultrastrong coupling regime.We considered the effect of the counter-rotating wave terms in the interaction Hamiltonian and derived the master equation in the eigenpresentation.We found that photon blockade occurred in only one of the eigenmodes,and the counter-rotating wave terms enhanced the blockade by reducing the minimum value of the second-order correlation function.This study will be beneficial for the design of single-photon devices in circuit QED systems,especially in the ultrastrong coupling regime.展开更多
We present work on a cavity-driven QED system combining an asymmetrical Fabry–Perot cavity and N two-level atoms(TLAs)and show the convenience of simplifying from distinguishable atoms to undistinguishable bosons whe...We present work on a cavity-driven QED system combining an asymmetrical Fabry–Perot cavity and N two-level atoms(TLAs)and show the convenience of simplifying from distinguishable atoms to undistinguishable bosons when the atoms are prepared in the same initial state.Such simplification is valid even when the atoms are not prepared in the inphase condition,since any partial in-phase initial state will evolve into the ground state through a relaxation process.Thus,we get a reduced group of differential equations by introducing the Dicke states,and the under-zero Lyapunov exponents verify its stability.We also work out the collective unconventional photon blockade(UCPB)and get two kinds of giant nonreciprocal UCPBs(NUCPBs)in the weak-driving approximation.Results show that we can employ N noninteracting bosonic atoms to generate a collective UCPB instead of a monoatomic UCPB as the UCPB conditions do not vary with the number of atoms.Furthermore,the forward giant NUCPB only occurring for N larger than a certain number as well as the backward giant NUCPB are controllable by the cavity asymmetry and by the number of atoms.Our findings suggest a prospective approach to the generation of quantum nonreciprocity by N identical atoms.展开更多
Dear Editor,Lymphocyte activation gene 3(LAG3),the third established target for immune checkpoint blockade therapy,suppresses T cell function by binding to major histocompatibility complex classⅡ(MHCⅡ).Despite its s...Dear Editor,Lymphocyte activation gene 3(LAG3),the third established target for immune checkpoint blockade therapy,suppresses T cell function by binding to major histocompatibility complex classⅡ(MHCⅡ).Despite its significant therapeutic potential in cancer immunotherapy and the substantial attention it has received from academia and industry,the molecular mechanisms of LAG3-mediated immunosuppression remain poorly understood,primarily because of its unique ligand-binding characteristics and intracellular domains[1].展开更多
Objectives:Immunotherapy based on immune checkpoint blockade(ICB)has become a key treatment for melanoma.However,the increasing number of cases of melanoma resistant to immunotherapy highlights the need to develop met...Objectives:Immunotherapy based on immune checkpoint blockade(ICB)has become a key treatment for melanoma.However,the increasing number of cases of melanoma resistant to immunotherapy highlights the need to develop methods to overcome this resistance.This study aims to collect the most recent information on melanoma immunotherapy,discuss potential strategies to overcome resistance to immunotherapy,and identify areas that require further analysis.Methods:To achieve this goal,scientific publications from 2021-2024 available in PubMed and Google Scholar databases were analyzed.The databases were searched using the following terms:“melanoma”,“immunotherapy”,“Immune Checkpoint Blockade”,and“immunoresistance”.Results:The results of preclinical and early-stage clinical research indicate the potential application of tank-binding kinase 1(TBK-1),fecal microbiota transplant(FMT),Toll-like Receptor 9(TLR9),lipid nanoparticles(LNPs)containing a stimulator of an interferon gene agonist(STING),BRAF inhibitors,Lymphocyte Activation Gene(LAG-3),T-Cell Immunoglobulin and ITIM Domain(TIGIT),and oncolytic viruses(OVs)as potential methods to enhance melanoma sensitivity to ICB.Discussion:To optimize immunotherapy,further research is needed to determine the detailed mechanisms of action,safety profiles,tolerability,and precise patient selection criteria for methods capable of overcoming melanoma’s immunoresistance.展开更多
In this retrospective study, we evaluated and compared the efficacy and toxicities of maximal androgen blockade （MAB） versus castration alone in Chinese patients with advanced prostate cancer. From 1996 to 2004, 608...In this retrospective study, we evaluated and compared the efficacy and toxicities of maximal androgen blockade （MAB） versus castration alone in Chinese patients with advanced prostate cancer. From 1996 to 2004, 608 patients with advanced prostate cancer were included in the study. Patients were retrospectively divided into two groups according to different therapeutic regimens. Of the 608 patients, 300 patients were treated with MAB （castration plus nonsteroidal antiandrogens） and the remaining 308 were treated with castration alone. The 2- and 5-year overall survival rates of these patients were 73.7% and 56%, respectively. Multivariate analysis showed that, in patients with metastatic prostate cancer, MAB was associated with not only the improvement of progression-free survival （PFS） （increased by 10 months） but also a 20.6% reduction in mortality risk compared with castration alone. In contrast, the efficacy of MAB was not superior to castration alone for patients with nonmetastatic prostate cancer. Interestingly, among patients with MAB, those using bicalutamide had a longer PFS than those using flutamide; this was especially so in patients with metastatic prostate cancer. Almost all of the toxicities due to the hormone therapy were mild to moderate and manageable. To conclude, in China, hormone therapies, including MAB and castration alone, have been standard treatments for advanced prostate cancer. For patients with nonmetastatic prostate cancer, castration alone might be adequately practical and efficient. In patients with metastatic prostate cancer, however, MAB has superior efficacy over castration alone. It is clear that MAB should be considered the first-line standard treatment for patients with metastatic prostate cancer.展开更多
The current blockade mechanism for λ -DNA translocation under electrical field is investigated through solid-state nanopores with different pore thicknesses. The conductance of a nanopore system mainly consists of t...The current blockade mechanism for λ -DNA translocation under electrical field is investigated through solid-state nanopores with different pore thicknesses. The conductance of a nanopore system mainly consists of the contribution of the pore and access region, and the latter becomes dominant when the nanopore thickness gradually decreases to atomic layer thickness. Based on the existing model of nanopore resistance, a simplified model which describes the relative current blockade during the X-DNA translocation through the nanopores is deduced to quantitatively present the relationship between nanopore thickness and relative current blockade. Results show that the relative current blockade is effectively increased by reducing the nanopore diameter but it decreases with the decreasing nanopore thickness. A two-stage schematic is proposed to increase the relative current blockade by setting a much smaller resistance region. Experimental results show a 21. 9% increase in the relative current blockade with the proposed schematic.展开更多
Epidermal growth factor receptor(EGFR)has been an attractive target for treatment of epithelial cancers,including colorectal cancer(CRC).Evidence from clinical trials indicates that cetuximab and panitumumab(antiEGFR ...Epidermal growth factor receptor(EGFR)has been an attractive target for treatment of epithelial cancers,including colorectal cancer(CRC).Evidence from clinical trials indicates that cetuximab and panitumumab(antiEGFR monoclonal antibodies)have clinical activity in patients with metastatic CRC.The discovery of intrinsic EGFR blockade resistance in Kirsten RAS(KRAS)-mutant patients led to the restriction of anti-EGFR antibodies to KRAS wild-type patients by Food and Drug Administration and European Medicine Agency.Studies have since focused on the evaluation of biomarkers to identify appropriate patient populations that may benefit from EGFR blockade.Accumulating evidence suggests that patients with mutations in EGFR downstream signaling pathways including KRAS,BRAF,PIK3CA and PTEN could be intrinsically resistant to EGFR blockade.Recent whole genome studies also suggest that dynamic alterations in signaling pathways downstream of EGFR leads to distinct oncogenic signatures and subclones which might have some impact on emerging resistance in KRAS wild-type patients.While anti-EGFR monoclonal antibodies have a clear potential in the management of a subset of patients with metastatic CRC,further studies are warranted to uncover exact mechanisms related to acquired resistance to EGFR blockade.展开更多
The disease burden related to hepatocellular carcinoma(HCC) is increasing. Most HCC patients are diagnosed at the advanced stage and multikinase inhibitors have been the only treatment choice for them. Recently, the a...The disease burden related to hepatocellular carcinoma(HCC) is increasing. Most HCC patients are diagnosed at the advanced stage and multikinase inhibitors have been the only treatment choice for them. Recently, the approval of immune checkpoint inhibitors(ICIs) has provided a new therapeutic strategy for HCC. It is noteworthy that the positive outcomes of the phase Ⅲ clinical trial IMBrave150 [atezolizumab(anti-programmed cell death ligand 1 antibody) combined with bevacizumab(anti-vascular endothelial growth factor monoclonal antibody)],showed that overall survival and progression-free survival were significantly better with sorafenib. This combination therapy has become the new standard therapy for advanced HCC and has also attracted more attention in the treatment of HCC with anti-angiogenesis-immune combination therapy. Currently, the synergistic antitumor efficacy of this combination has been shown in many preclinical and clinical studies. In this review, we discuss the mechanism and clinical application of anti-angiogenics and immunotherapy in HCC, outline the relevant mechanism and rationality of the combined application of antiangiogenics and ICIs, and point out the existing challenges of the combination therapy.展开更多
BACKGROUND Few studies have examined the specific efficacy of deep neuromuscular blockade(NMB)combined with pneumoperitoneal pressure reduction in laparoscopic radical gastrectomy(LRG)in the elderly.AIM To investigate...BACKGROUND Few studies have examined the specific efficacy of deep neuromuscular blockade(NMB)combined with pneumoperitoneal pressure reduction in laparoscopic radical gastrectomy(LRG)in the elderly.AIM To investigate the application effect of deep neuromuscular blockade(NMB)combined with reduced pneumoperitoneum pressure in LRG for gastric cancer(GC)in elderly patients and its influence on inflammation.METHODS Totally 103 elderly patients with GC treated in our hospital between January 2020 and January 2022 were retrospectively analyzed.Among them,45 patients treated with surgery based on deep NMB and conventional pneumoperitoneum pressure were assigned to the control group,while the rest of the 58 patients who underwent surgery based on deep NMB and reduced pneumoperitoneum pressure were assigned to the observation group.The two groups were compared in the changes of the Leiden-surgical rating scale score,serum tumor necrosis fact-α(TNF-α)and interleukin 6(IL-6)before and after therapy.The visual analogue scale(VAS)was adopted for evaluating the shoulder pain of patients at 8 h,24 h and 48 h after the operation.The driving pressure of the two groups at different time points was also compared.Additionally,the operation time,pneumoperitoneum time,infusion volume,blood loss,extubation time after surgery,residence time in the resuscitation room,TOF%=90%time and post-anesthetic recovery room(PACU)stay time were all recorded,and adverse PACU-associated respiratory events were also recorded.The postoperative hospitalization time and postoperative expenses of the two groups were counted and compared.RESULTS No significant difference was found between the two groups at the time of skin incision,60 minutes since the operation and abdominal closure after surgery(P>0.05).The observation group exhibited significantly lower VAS scores than the control group at 24 and 48h after surgery(P<0.05).Additionally,the observation group had significantly lower driving pressure than the control group at 5 min and 60 min after the establishment of pneumoperitoneum(P<0.05).Additionally,the two groups were similar in terms of the operation time,pneumoperitoneum time,infusion volume,blood loss,extubation time after surgery,residence time in the resuscitation room and TOF%=90%time(P>0.05),and the observation group showed significantly lower TNF-αand IL-6 Levels than the control group at 24 h after therapy(P<0.05).Moreover,the incidence of adverse events was not significantly different between the two groups(P>0.05),and the observation group experienced significantly less hospitalization time and postoperative expenses than the control group(P<0.05).CONCLUSION Deep NMB combined with reduced pneumoperitoneum pressure can decrease the VAS score of shoulder pain and inflammatory reaction,without hindering the surgical vision and increasing adverse PACU-associated respiratory events,and can thus shorten the hospitalization time and treatment cost for patient.展开更多
During the past decades,the treatment of hepatocellular carcinoma(HCC)has been limited to surgical resection and liver transplantation,but the prognosis is still poor.Recently,tumor immunotherapy,particularly immune c...During the past decades,the treatment of hepatocellular carcinoma(HCC)has been limited to surgical resection and liver transplantation,but the prognosis is still poor.Recently,tumor immunotherapy,particularly immune checkpoints programmed cell death-1/programmed cell death ligand-1(PD-1/PD-L1)blockade,brings a breakthrough for HCC[1,2].However,anti-PD-1/PD-L1 immunotherapy is not satisfactory and the response rates were between 20%and 30%[3].How to improve the efficacy of PD-1/PD-L1blockade is the main issue.展开更多
BACKGROUND In recent years,immune checkpoint inhibitors(ICIs)have demonstrated remarkable efficacy across diverse malignancies.Notably,in patients with advanced gastric cancer,the use of programmed death 1(PD-1)blocka...BACKGROUND In recent years,immune checkpoint inhibitors(ICIs)have demonstrated remarkable efficacy across diverse malignancies.Notably,in patients with advanced gastric cancer,the use of programmed death 1(PD-1)blockade has significantly prolonged overall survival,marking a pivotal advancement comparable to the impact of Herceptin over the past two decades.While the therapeutic benefits of ICIs are evident,the increasing use of immunotherapy has led to an increase in immune-related adverse events.CASE SUMMARY This article presents the case of a patient with advanced gastric cancer and chronic plaque psoriasis.Following sintilimab therapy,the patient developed severe rashes accompanied by cytokine release syndrome(CRS).Fortunately,effective management was achieved through the administration of glucocorticoid,tocilizumab,and acitretin,which resulted in favorable outcomes.CONCLUSION Glucocorticoid and tocilizumab therapy was effective in managing CRS after PD-1 blockade therapy for gastric cancer in a patient with chronic plaque psoriasis.展开更多
During the past three decades,studies have shown that tumor cells could"manipulate"host immunity to escape the immune defenses in the tumor microenvironment.One of the most important underlying mechanisms is...During the past three decades,studies have shown that tumor cells could"manipulate"host immunity to escape the immune defenses in the tumor microenvironment.One of the most important underlying mechanisms is immune-suppression regulated by programmed cell death-1 or its ligand 1(PD-1/PD-L1),which makes PD-1/PD-L1 blockadea promising target of cancer immune-therapy.Tumors could suppress immuno-response of T cells by activating PD-1/PD-L1 signaling pathway.Therefore,inhibiting the interaction between PD-1 and PD-L1 could reconstitute the enduring antitumor immunity in the tumor microenvironment via enhancing the T-cell response,there after augmenting the endogenous antitumor force of the immune system.Along these lines,inhibitors of PD-1/PD-L1 has been applied in multiple clinical trials against various types of tumors.Recent studies indicated that PD-1/PD-L1 blockade have demonstrated high efficacy and safety against melanoma,lung,kidney and several other solid tumors,as well as hematological malignancies.Nevertheless,the efficacy of this checkpoint blockade approach is not universal.Some investigation suggested that lack of responses to anti-PD-1/PD-L1 therapy of patients without PD-1/PD-L1 over-expression was expected.In this review,we summarize the history and current understanding of multiple intrinsic and extrinsic mechanisms via which PD-1/PD-L1 is regulated and research advances in preclinical/clinical aspects of PD-1/PD-L1,as well as significance and perspectives regarding the PD-1/PD-L1 blockade in immune-antitumor therapy.展开更多
基金The National Natural Science Foundation of China(Nos.82473864,82400095)the Natural Science Foundation of Jiangsu Province(No.BK20231009)+1 种基金the National Center of Technology Innovation for Biopharmaceuticals(No.NCTIB2022HS01015)"Double First-Class"Initiative Program in China Pharmaceutical University and the National Innovation and Entrepreneurship Training Programfor Undergraduate(Nos.202310316007Z,2023103161133,2023103161333)are acknowledged for providing financial support for this work.
文摘Doxorubicin(DOX)is known to elicit potent antitumor immune responses through the induction of immunogenic cell death(ICD).However,its therapeutic efficacy is undermined by the adaptive upregulation of programmed cell death ligand 1(PD-L1),which hijacked the antitumor immunity.In this study,we developed a reactive oxygen species(ROS)-responsive dihydroartemisinin(DHA)prodrug to facilitate the delivery of DOX via hydrophobic and electrostatic interactions.Upon internalization by tumor cells,the nanoparticles(NPs)preferentially accumulated in endoplasmic reticulum(ER),exacerbating ER stress and amplifying ICD to enhance tumor immunogenicity.Simultaneously,the oxidative intracellular environment trigged the degradation of NPs,releasing DHA,which downregulated PD-L1 by disrupting signal transducer and activator of transcription 3(STAT3)phosphorylation and inactivating the nuclear factor kappa-B(NF-κB)pathway.Consequently,the effective PD-L1 blockade and robust ICD response,synergistically inhibited breast cancer progression,significantly enhancing the chemo-immunotherapy efficacy of doxorubicin.
基金supported by the National Key Research and Development Program of China(No.2022YFE0102100)the National Natural Science Foundation of China(Nos.U22A20307 and 81930041)。
文摘Dysfunction of anti-tumor immune responses is crucial for cancer progression. Immune checkpoint blockade(ICB), which can potentiate T cell responses, is an effective strategy for the normalization of host anti-tumor immunity. In recent years, immune checkpoints, expressed on both tumor cells and immune cells, have been identified;some of them have exhibited potential druggability and have been approved by the US Food and Drug Administration(FDA) for clinical treatment. However, limited responses and immune-related adverse events(ir AEs) cannot be ignored. This review outlines the development and applications of ICBs, potential strategies for overcoming resistance, and future directions for ICB-based cancer immunotherapy.
基金supported by Techpool Bio-Pharma Co.,Ltd.(grant no.AKR-S005).
文摘Objective:To investigate the anti-tumor effects of an E1B55KD-deleted oncolytic adenovirus,H101,in combination with a humanized anti-PD-1(Programmed cell death protein 1)monoclonal antibody,Camrelizumab.Methods:Anti-tumor efficacy of intratumoral injection of H101 or/and intraperitoneal injection of Camrelizumab were evaluated in an immune system humanized NOD Prkdc^(scid) Il2rg^(-/-)mice subcutaneous(S.C.)tumor model,established with human glioblastoma of unknown origin cell line U87-MG,and human bladder cancer cell line T24 and YTS-1.The mechanism by which H101 induced anti-tumor immunity were also investigated.Results:Combining H101 with Camrelizumab demonstrated more potent anti-tumor effects than monotherapy in mouse S.C.tumor model.Increased tumor-infiltrating T cells were observed in the combined treatment group.H101 infection decreased the expression of CD47 in cancer cells,thereby promoting macrophages to phagocytose cancer cells.Following the H101-mediated activation of macrophages,increased levels of cytokines,including TNF,IL-12 and IFN-γwere observed.Moreover,when induced THP-1 cells were co-cultured with H101-treated cancer cells,expression of IFN-γwas increased in T cells.Elimination of IL-12 using an anti-IL-12 antibody abolished IFN-γproduction from T cells.In addition,infection with H101 increased PD-L1 expression in YTS-1 cells.These results suggested that H101 may act synergistically to enhance the therapeutic efficacy of PD-1 blockade in cancer via suppressing CD47 signaling,which may promote macrophages to phagocytose tumor cells and activate CD8^(+)T cells.Conclusion:The combination of H101 with PD-1 blockade exhibits potential as a novel strategy for the treatment of cancer.
文摘BACKGROUND Bradycardia,renal failure,atrioventricular nodal blockade,shock,and hyper-kalemia(BRASH)syndrome is an acronym used to describe a constellation of BRASH.It is an underrecognized phenomenon that can be deadly if not appro-priately managed in a timely manner.This case highlights the importance of rapid diagnosis and reviews a multitude of treatment options in a uniquely severe case of BRASH syndrome.CASE SUMMARY We present a case of a 54-year-old male on a beta-blocker and angiotensin-con-verting enzyme inhibitor who presented with one day history of nausea,vomi-ting,and shortness of breath.Upon presentation,he was bradycardic and hypotensive,requiring transcutaneous pacing.Initial electrocardiogram showed atrial fibrillation with ventricular rate in 30’s.He was found to have acute kidney injury,hyperkalemia,and metabolic acidosis.He was successfully treated with multiple potassium lowering agents,continuous renal replacement therapy,four pressors,mechanical ventilation,and transvenous pacing with complete recovery prior to discharge.CONCLUSION Increased awareness of BRASH syndrome may improve outcomes through timely diagnosis and aggressive intervention.
基金National Natural Science Foundation of China(Grant Nos.:82274154,82304792)Natural Science Foundation of Tianjin Municipality(GrantNos.:23JCzXJC00150+1 种基金23JCJQjC00040)China Postdoctoral Science Foundation(Grant Nos.:2023M732627,2024T170657).
文摘Therapeutic antibodies of targeting the programmed cell death protein 1(PD-1)/programmed death-ligand 1(PD-L1)pathway are used in hepatocellular carcinoma(HCC)treatment,but are limited by low response rates and immune-related toxicity[1].Searching for treatment approaches to combine with PD-1/PD-L1 blockade may potentially enhance the efficacy of PD-1/PD-L1 blockade and reduce its side effects.
基金supported by the National Natural Science Foundation of China(Nos.U23A20591 and 52273158)the Science and Technology Development Program of Jilin Province(Nos.20240101002JJ and 20210504001GH).
文摘Tumor blockade therapy inhibits tumor progression by cutting off essential supplies of nutrients,oxygen,and biomolecules from the surrounding microenvironments.Inspired by natural processes,tumor biomineralization has evolved due to its biocompatibility,self-reinforcing capability,and penetrationindependent mechanism.However,the selective induction of tumor biomineralization using synthetic tools presents a significant challenge.Herein,a metabolic glycoengineering-assistant tumor biomineralization strategy was developed.Specifically,the azido group(N_(3))was introduced onto the cytomembrane by incubating tumor cells with glycose analog Ac4ManNAz.In addition,a bisphosphonate-containing polymer,dibenzocyclooctyne-poly(ethylene glycol)-alendronate(DBCO-PEG-ALN,DBPA)was synthesized,which attached to the tumor cell surface via"click chemistry"reaction between DBCO and N_(3).Subsequently,the bisphosphonate group on the cell surface chelated with positively charged ions in the microenvironments,triggering a consecutive process of biomineralization.This physical barrier significantly reduced tumor cell viability and mobility in a calcium ion concentration-dependent manner,suggesting its potential as an effective anti-tumor strategy for in vivo applications.
基金financially supported by the National Natural Science Foundation of China(82173769)Tianjin Science Foundation for Distinguished Young Scholars(24JCJQJC00050)+2 种基金Applied Basic Research Multi-Investment Foundation of Tianjin(21JCYBJC01540)the National Natural Science Foundation of China(82300336)the Science&Technology Development Fund of Tianjin Education Commission for Higher Education(2019KJ178).
文摘Mitochondria provides adenosine triphosphate for multiple vital movements to ensure tumor cell proliferation.Compared to the broadly used method of inducing DNA replication arrest to kill cancer,inducing mitochondria damage to cause energy shortage is quite promising as it can inhibit tumor cell bioactivities,increase intracellular accumulation of toxic drugs,eventually sensitize chemotherapy and even reverse drug resistance.Breaking the balance of glutathione(GSH)and reactive oxygen species(ROS)contents have been proven efficient in destroying mitochondria respectively.Herein,apigenin,a GSH efflux reagent,and 2-deoxy-5-fluorouridine 5-monophosphate sodium salt(FdUMP)that could induce toxic ROS were co-delivered by constructed lipid nanoparticles,noted as Lip@AF.An immune-checkpoint inhibition reagent CD276 antibody was modified onto the surface of Lip@AF with high reaction specificity(noted asαCD276-Lip@AF)to enhance the recognition of immune cells to tumor.Results showed that the redox balancewas destroyed,leading to severe injury to mitochondria and cell membrane.Furthermore,synergistic DNA/RNA replication inhibition caused by inhibiting the function of thymidylate synthase were observed.Eventually,significantly enhanced cytotoxicity was achieved by combining multiple mechanisms including ferroptosis,apoptosis and pyroptosis.In vivo,strengthen tumor growth inhibitionwas achieved byαCD276-Lip@AF with high biosafety,providing new sights in enhancing chemotherapy sensitiveness and achieving high-performance chemo-immunotherapy.
基金Supported by the Science and Technology Program of Guangzhou,No.202201020024.
文摘BACKGROUND Irreversible electroporation(IRE)represents an innovative localized technique for tumor ablation,possessing the capacity to activate the immune response of the host.However,this method alone is inadequate to halt cancer progression,necessitating the integration of additional strategies to achieve effective immuno-therapy.AIM To investigate the effects and underlying mechanisms of antitumor immunity derived from the synergistic application of IRE and anti-programmed cell death protein 1(PD-1)therapy within a murine model of hepatocellular carcinoma.METHODS C57BL-6 mice with tumor growth were divided into four separate cohorts:Control group;IRE group;Anti-PD-1 group;And IRE+anti-PD-1 group.The infiltration levels of T,B,and natural killer cells within the tumors,as well as the plasma concentrations of T helper type 1 cytokines(interleukin-2,interferon-γ,and tumor necrosis factor-β),were evaluated.Real-time polymerase chain reaction was utilized to quantify the expression of cluster of differentiation(CD)8(a marker indicative of CD8+T cells)in the tumor specimens of the mice at various temporal intervals.Tumor growth trajectories were charted.RESULTS The results indicated that the IRE+anti-PD-1 group exhibited significantly heightened percentages of T lymphocyte infiltration,particularly CD4+and CD8+T cells,when compared to the control cohort.Additionally,this group displayed increased infiltration of natural killer and B cells,augmented cytokine levels,and elevated CD8 messenger RNA expression.A marked decrease in tumor volume was noted in the IRE+anti-PD-1 group,indicating enhanced therapeutic efficacy.CONCLUSION The combined application of IRE and checkpoint blockade elicits an antitumor immune response,leading to a more substantial reduction in tumor volume and improved therapeutic outcomes,thereby establishing a novel avenue for the ablation and immunotherapy of hepatocellular carcinoma.
基金supported by the National Science Foundation of China(Grant No.12105026)Climbing Plan of Changchun University(Grant No.ZKP202010)Educational Commission of Jilin Province of China(Grant No.JJKH20230663KJ)。
文摘The circuit quantum electrodynamics(QED)system has brought us into an ultrastrong and deep coupling regime in the light-matter interaction community,in which the quantum effect has attracted significant interest.In this study,we theoretically investigated the photon blockade phenomenon in a double-transmon system operating in an ultrastrong coupling regime.We considered the effect of the counter-rotating wave terms in the interaction Hamiltonian and derived the master equation in the eigenpresentation.We found that photon blockade occurred in only one of the eigenmodes,and the counter-rotating wave terms enhanced the blockade by reducing the minimum value of the second-order correlation function.This study will be beneficial for the design of single-photon devices in circuit QED systems,especially in the ultrastrong coupling regime.
基金Project supported by the National Natural Science Foundation of China(Grant Nos.12164022 and 12174288)Natural Science Foundation of Jiangxi Province of China(Grant No.20232BAB201044)+1 种基金Scientific Research Foundation of the Education Department of Jiangxi Province of China(Grant No.GJJ211039)China Postdoctoral Science Foundation(Grant No.2023M732028)。
文摘We present work on a cavity-driven QED system combining an asymmetrical Fabry–Perot cavity and N two-level atoms(TLAs)and show the convenience of simplifying from distinguishable atoms to undistinguishable bosons when the atoms are prepared in the same initial state.Such simplification is valid even when the atoms are not prepared in the inphase condition,since any partial in-phase initial state will evolve into the ground state through a relaxation process.Thus,we get a reduced group of differential equations by introducing the Dicke states,and the under-zero Lyapunov exponents verify its stability.We also work out the collective unconventional photon blockade(UCPB)and get two kinds of giant nonreciprocal UCPBs(NUCPBs)in the weak-driving approximation.Results show that we can employ N noninteracting bosonic atoms to generate a collective UCPB instead of a monoatomic UCPB as the UCPB conditions do not vary with the number of atoms.Furthermore,the forward giant NUCPB only occurring for N larger than a certain number as well as the backward giant NUCPB are controllable by the cavity asymmetry and by the number of atoms.Our findings suggest a prospective approach to the generation of quantum nonreciprocity by N identical atoms.
文摘Dear Editor,Lymphocyte activation gene 3(LAG3),the third established target for immune checkpoint blockade therapy,suppresses T cell function by binding to major histocompatibility complex classⅡ(MHCⅡ).Despite its significant therapeutic potential in cancer immunotherapy and the substantial attention it has received from academia and industry,the molecular mechanisms of LAG3-mediated immunosuppression remain poorly understood,primarily because of its unique ligand-binding characteristics and intracellular domains[1].
文摘Objectives:Immunotherapy based on immune checkpoint blockade(ICB)has become a key treatment for melanoma.However,the increasing number of cases of melanoma resistant to immunotherapy highlights the need to develop methods to overcome this resistance.This study aims to collect the most recent information on melanoma immunotherapy,discuss potential strategies to overcome resistance to immunotherapy,and identify areas that require further analysis.Methods:To achieve this goal,scientific publications from 2021-2024 available in PubMed and Google Scholar databases were analyzed.The databases were searched using the following terms:“melanoma”,“immunotherapy”,“Immune Checkpoint Blockade”,and“immunoresistance”.Results:The results of preclinical and early-stage clinical research indicate the potential application of tank-binding kinase 1(TBK-1),fecal microbiota transplant(FMT),Toll-like Receptor 9(TLR9),lipid nanoparticles(LNPs)containing a stimulator of an interferon gene agonist(STING),BRAF inhibitors,Lymphocyte Activation Gene(LAG-3),T-Cell Immunoglobulin and ITIM Domain(TIGIT),and oncolytic viruses(OVs)as potential methods to enhance melanoma sensitivity to ICB.Discussion:To optimize immunotherapy,further research is needed to determine the detailed mechanisms of action,safety profiles,tolerability,and precise patient selection criteria for methods capable of overcoming melanoma’s immunoresistance.
基金Acknowledgment We thank Professor Qiao Zhou from the Department of Pathology, West China Hospital, Dr Jing Gong from the Laboratory of Pathology, the State Key Laboratory of Biotherapy, and many other clinicians from the Department of Urology, West China hospital for their kind assistance. This work was supported by the National Natural Science Foundation of China （No. NSFC30700977, No. NSFC30800637 and No. NSFC30871383）.
文摘In this retrospective study, we evaluated and compared the efficacy and toxicities of maximal androgen blockade （MAB） versus castration alone in Chinese patients with advanced prostate cancer. From 1996 to 2004, 608 patients with advanced prostate cancer were included in the study. Patients were retrospectively divided into two groups according to different therapeutic regimens. Of the 608 patients, 300 patients were treated with MAB （castration plus nonsteroidal antiandrogens） and the remaining 308 were treated with castration alone. The 2- and 5-year overall survival rates of these patients were 73.7% and 56%, respectively. Multivariate analysis showed that, in patients with metastatic prostate cancer, MAB was associated with not only the improvement of progression-free survival （PFS） （increased by 10 months） but also a 20.6% reduction in mortality risk compared with castration alone. In contrast, the efficacy of MAB was not superior to castration alone for patients with nonmetastatic prostate cancer. Interestingly, among patients with MAB, those using bicalutamide had a longer PFS than those using flutamide; this was especially so in patients with metastatic prostate cancer. Almost all of the toxicities due to the hormone therapy were mild to moderate and manageable. To conclude, in China, hormone therapies, including MAB and castration alone, have been standard treatments for advanced prostate cancer. For patients with nonmetastatic prostate cancer, castration alone might be adequately practical and efficient. In patients with metastatic prostate cancer, however, MAB has superior efficacy over castration alone. It is clear that MAB should be considered the first-line standard treatment for patients with metastatic prostate cancer.
基金The Natural Science Foundation of Jiangsu Province(No.BK20160935)the Natural Science Foundation of Higher Education Institutions of Jiangsu Province(No.16KJB460015)
文摘The current blockade mechanism for λ -DNA translocation under electrical field is investigated through solid-state nanopores with different pore thicknesses. The conductance of a nanopore system mainly consists of the contribution of the pore and access region, and the latter becomes dominant when the nanopore thickness gradually decreases to atomic layer thickness. Based on the existing model of nanopore resistance, a simplified model which describes the relative current blockade during the X-DNA translocation through the nanopores is deduced to quantitatively present the relationship between nanopore thickness and relative current blockade. Results show that the relative current blockade is effectively increased by reducing the nanopore diameter but it decreases with the decreasing nanopore thickness. A two-stage schematic is proposed to increase the relative current blockade by setting a much smaller resistance region. Experimental results show a 21. 9% increase in the relative current blockade with the proposed schematic.
文摘Epidermal growth factor receptor(EGFR)has been an attractive target for treatment of epithelial cancers,including colorectal cancer(CRC).Evidence from clinical trials indicates that cetuximab and panitumumab(antiEGFR monoclonal antibodies)have clinical activity in patients with metastatic CRC.The discovery of intrinsic EGFR blockade resistance in Kirsten RAS(KRAS)-mutant patients led to the restriction of anti-EGFR antibodies to KRAS wild-type patients by Food and Drug Administration and European Medicine Agency.Studies have since focused on the evaluation of biomarkers to identify appropriate patient populations that may benefit from EGFR blockade.Accumulating evidence suggests that patients with mutations in EGFR downstream signaling pathways including KRAS,BRAF,PIK3CA and PTEN could be intrinsically resistant to EGFR blockade.Recent whole genome studies also suggest that dynamic alterations in signaling pathways downstream of EGFR leads to distinct oncogenic signatures and subclones which might have some impact on emerging resistance in KRAS wild-type patients.While anti-EGFR monoclonal antibodies have a clear potential in the management of a subset of patients with metastatic CRC,further studies are warranted to uncover exact mechanisms related to acquired resistance to EGFR blockade.
基金Guangdong Basic and Applied Basic Research Foundation,No.2019A1515110654the National Natural Science Foundation of China,No.82103448China Organ Transplantation Development Foundation,No.YZLC-2021-003.
文摘The disease burden related to hepatocellular carcinoma(HCC) is increasing. Most HCC patients are diagnosed at the advanced stage and multikinase inhibitors have been the only treatment choice for them. Recently, the approval of immune checkpoint inhibitors(ICIs) has provided a new therapeutic strategy for HCC. It is noteworthy that the positive outcomes of the phase Ⅲ clinical trial IMBrave150 [atezolizumab(anti-programmed cell death ligand 1 antibody) combined with bevacizumab(anti-vascular endothelial growth factor monoclonal antibody)],showed that overall survival and progression-free survival were significantly better with sorafenib. This combination therapy has become the new standard therapy for advanced HCC and has also attracted more attention in the treatment of HCC with anti-angiogenesis-immune combination therapy. Currently, the synergistic antitumor efficacy of this combination has been shown in many preclinical and clinical studies. In this review, we discuss the mechanism and clinical application of anti-angiogenics and immunotherapy in HCC, outline the relevant mechanism and rationality of the combined application of antiangiogenics and ICIs, and point out the existing challenges of the combination therapy.
基金Zhejiang Health Science and Technology Plan 2022,No.2022KY320。
文摘BACKGROUND Few studies have examined the specific efficacy of deep neuromuscular blockade(NMB)combined with pneumoperitoneal pressure reduction in laparoscopic radical gastrectomy(LRG)in the elderly.AIM To investigate the application effect of deep neuromuscular blockade(NMB)combined with reduced pneumoperitoneum pressure in LRG for gastric cancer(GC)in elderly patients and its influence on inflammation.METHODS Totally 103 elderly patients with GC treated in our hospital between January 2020 and January 2022 were retrospectively analyzed.Among them,45 patients treated with surgery based on deep NMB and conventional pneumoperitoneum pressure were assigned to the control group,while the rest of the 58 patients who underwent surgery based on deep NMB and reduced pneumoperitoneum pressure were assigned to the observation group.The two groups were compared in the changes of the Leiden-surgical rating scale score,serum tumor necrosis fact-α(TNF-α)and interleukin 6(IL-6)before and after therapy.The visual analogue scale(VAS)was adopted for evaluating the shoulder pain of patients at 8 h,24 h and 48 h after the operation.The driving pressure of the two groups at different time points was also compared.Additionally,the operation time,pneumoperitoneum time,infusion volume,blood loss,extubation time after surgery,residence time in the resuscitation room,TOF%=90%time and post-anesthetic recovery room(PACU)stay time were all recorded,and adverse PACU-associated respiratory events were also recorded.The postoperative hospitalization time and postoperative expenses of the two groups were counted and compared.RESULTS No significant difference was found between the two groups at the time of skin incision,60 minutes since the operation and abdominal closure after surgery(P>0.05).The observation group exhibited significantly lower VAS scores than the control group at 24 and 48h after surgery(P<0.05).Additionally,the observation group had significantly lower driving pressure than the control group at 5 min and 60 min after the establishment of pneumoperitoneum(P<0.05).Additionally,the two groups were similar in terms of the operation time,pneumoperitoneum time,infusion volume,blood loss,extubation time after surgery,residence time in the resuscitation room and TOF%=90%time(P>0.05),and the observation group showed significantly lower TNF-αand IL-6 Levels than the control group at 24 h after therapy(P<0.05).Moreover,the incidence of adverse events was not significantly different between the two groups(P>0.05),and the observation group experienced significantly less hospitalization time and postoperative expenses than the control group(P<0.05).CONCLUSION Deep NMB combined with reduced pneumoperitoneum pressure can decrease the VAS score of shoulder pain and inflammatory reaction,without hindering the surgical vision and increasing adverse PACU-associated respiratory events,and can thus shorten the hospitalization time and treatment cost for patient.
基金supported by grants from the CAMS Innovation Fund for Medical Sciences(2016-I2M-1-001)the National High-tech Research and Development Projects(863)(2015AA020303)the National Natural Science Foundation of China(31500818)
文摘During the past decades,the treatment of hepatocellular carcinoma(HCC)has been limited to surgical resection and liver transplantation,but the prognosis is still poor.Recently,tumor immunotherapy,particularly immune checkpoints programmed cell death-1/programmed cell death ligand-1(PD-1/PD-L1)blockade,brings a breakthrough for HCC[1,2].However,anti-PD-1/PD-L1 immunotherapy is not satisfactory and the response rates were between 20%and 30%[3].How to improve the efficacy of PD-1/PD-L1blockade is the main issue.
基金Supported by Shaoxing Health Science and Technology Program,No.2022SY016,No.2022KY010.
文摘BACKGROUND In recent years,immune checkpoint inhibitors(ICIs)have demonstrated remarkable efficacy across diverse malignancies.Notably,in patients with advanced gastric cancer,the use of programmed death 1(PD-1)blockade has significantly prolonged overall survival,marking a pivotal advancement comparable to the impact of Herceptin over the past two decades.While the therapeutic benefits of ICIs are evident,the increasing use of immunotherapy has led to an increase in immune-related adverse events.CASE SUMMARY This article presents the case of a patient with advanced gastric cancer and chronic plaque psoriasis.Following sintilimab therapy,the patient developed severe rashes accompanied by cytokine release syndrome(CRS).Fortunately,effective management was achieved through the administration of glucocorticoid,tocilizumab,and acitretin,which resulted in favorable outcomes.CONCLUSION Glucocorticoid and tocilizumab therapy was effective in managing CRS after PD-1 blockade therapy for gastric cancer in a patient with chronic plaque psoriasis.
文摘During the past three decades,studies have shown that tumor cells could"manipulate"host immunity to escape the immune defenses in the tumor microenvironment.One of the most important underlying mechanisms is immune-suppression regulated by programmed cell death-1 or its ligand 1(PD-1/PD-L1),which makes PD-1/PD-L1 blockadea promising target of cancer immune-therapy.Tumors could suppress immuno-response of T cells by activating PD-1/PD-L1 signaling pathway.Therefore,inhibiting the interaction between PD-1 and PD-L1 could reconstitute the enduring antitumor immunity in the tumor microenvironment via enhancing the T-cell response,there after augmenting the endogenous antitumor force of the immune system.Along these lines,inhibitors of PD-1/PD-L1 has been applied in multiple clinical trials against various types of tumors.Recent studies indicated that PD-1/PD-L1 blockade have demonstrated high efficacy and safety against melanoma,lung,kidney and several other solid tumors,as well as hematological malignancies.Nevertheless,the efficacy of this checkpoint blockade approach is not universal.Some investigation suggested that lack of responses to anti-PD-1/PD-L1 therapy of patients without PD-1/PD-L1 over-expression was expected.In this review,we summarize the history and current understanding of multiple intrinsic and extrinsic mechanisms via which PD-1/PD-L1 is regulated and research advances in preclinical/clinical aspects of PD-1/PD-L1,as well as significance and perspectives regarding the PD-1/PD-L1 blockade in immune-antitumor therapy.
