Hepatocellular carcinoma(HCC)is a primary malignant tumor of the liver and one of the most common malignant tumors,as well as the third leading cause of cancer-related death.In recent years,immune checkpoint inhibitor...Hepatocellular carcinoma(HCC)is a primary malignant tumor of the liver and one of the most common malignant tumors,as well as the third leading cause of cancer-related death.In recent years,immune checkpoint inhibitors have emerged as a key strategy in cancer treatment.However,anti-programmed cell death 1/programmed death ligand 1 therapies,one of the main immunotherapeutic approaches,only elicit a response in only approximately 20%of advanced HCC.This suggests that there may be other immune checkpoints playing important roles in HCC immunotherapy.Recent studies have highlighted Signal regulatory protein alpha(SIRPα)is a phagocytic checkpoint in macrophages and other immune cells,as a promising novel therapeutic target in tumor immunotherapy.This review summarizes current progress on SIRPαin HCC and identifies key challenges for future related research.展开更多
In recent years,immune checkpoint molecules have made breakthroughs in the fields of inducing graft tolerance,tumor immune escape and preventing autoimmunity.These immunoregulatory factors,when combined with ligand,ca...In recent years,immune checkpoint molecules have made breakthroughs in the fields of inducing graft tolerance,tumor immune escape and preventing autoimmunity.These immunoregulatory factors,when combined with ligand,can transduce the inhibitory signal into cells to negatively regulate the immune response,which brings new enlightenment for the immune research of pregnancy and pregnancy complications.In this review,we reviewed the immunomodulatory effects of CTLA-4,PD-1 and Tim-3 in pregnancy,in order to evaluate their potential effects in pregnancy,and to provide a new direction for the immunotherapy of pregnancy complications.展开更多
One of the most prevalent malignant tumors worldwide,stomach cancer still has a high incidence and fatality rate in China,and the number of young people developing early-onset gastric cancer is steadily increasing.The...One of the most prevalent malignant tumors worldwide,stomach cancer still has a high incidence and fatality rate in China,and the number of young people developing early-onset gastric cancer is steadily increasing.The 5-year survival rate of stomach cancer is typically 30%–35%,the prognosis is bad,the patients’quality of life is low,and the progression of advanced gastric cancer cannot be effectively managed despite the use of surgical surgery,chemotherapy,and other medicines.We urgently need molecular biomarkers with high specificity and sensitivity to increase the early gastric cancer detection rate,extend patient survival,and improve patient quality of life.The initial diagnosis of gastric cancer primarily depends on gastroscopy and biopsy,and invasive procedures cause significant discomfort to patients.Similar to this,treating advanced and metastatic stomach cancer is a pressing issue that requires attention.More and more immune checkpoint molecules have been discovered,and corresponding inhibitors are gradually being applied to clinical diagnosis and treatment.Recently,some non-coding RNAs have begun to be used as new targets for the treatment of gastric cancer.Some non-coding RNAs are highly present in the serum or urine of gastric cancer patients and can be used as diagnostic markers or prognostic indicators.Many clinical trials targeting non-coding RNAs have also shown good therapeutic effects.In general,targeting non-coding RNAs has shown good therapeutic effects.The biomarkers for gastric cancer detection and treatment are reviewed in this article,focusing on the new non-coding RNAs used in diagnosis,prognosis,and treatment.Patients with stomach cancer should have access to more precise and efficient diagnosis and treatment choices as a result of ongoing technological advancements and thorough research.展开更多
To the editor:The liver’s immune-privileged status allows for a unique microenvironment that supports tumour growth and metastasis.In hepatocellular carcinoma(HCC),the balance between cytotoxic T lymphocytes and regu...To the editor:The liver’s immune-privileged status allows for a unique microenvironment that supports tumour growth and metastasis.In hepatocellular carcinoma(HCC),the balance between cytotoxic T lymphocytes and regulatory T cells plays a crucial role in determining patient outcomes.The expression of programmed cell death ligand 1(PD-1)and other immune checkpoint molecules contributes to a pro-tumourigenic microenvironment and is associated with poor prognosis.Additionally,the heterogeneity of the immune microenvironment adds complexity to disease progression and treatment response.展开更多
AIM: To explore the effects of interferon-α(IFN-α) application on peripheral circulating CD1αdendritic cells (DCs) in patients with chronic hepatitis B, and the expression of HLA-DR, CD80, and ICAM-1 on CD1αDCs in...AIM: To explore the effects of interferon-α(IFN-α) application on peripheral circulating CD1αdendritic cells (DCs) in patients with chronic hepatitis B, and the expression of HLA-DR, CD80, and ICAM-1 on CD1αDCs in order to explore the mechanism of immune modulation of IFN-α. METHODS: By flow cytometry technique, changes of CD1αDCs were monitored in 22 patients with chronic hepatitis B treated with IFN-αand in 16 such patients not treated with IFN-αwithin three months. Meanwhile, the expression of HLA-DR, CD80, and ICAM-1 on CD1αDCs was detected. RESULTS: In the group of IFN-αtreatment, the percentage of CD1αDCs in peripheral blood mono-nuclear cells was increased after three months of therapy. In patients who became negative for HBV-DNA after IFN-αtreatment, the increase of DCs was more prominent, while in control, these changes were not observed. Increased expression of HLA-DR, CD80, and ICAM-1 on CD1αDCs was also observed. CONCLUSION: CD1αDCs can be induced by IFN-αin vivo, and the immune related molecules such as HLA-DR, CD80, and ICAM-1 are up-regulated to some degree. This might be an important immune related mechanism of IFN-αtreatment for chronic hepatitis B.展开更多
The immune system as an important defense system of the body,bear the resistance to foreign pathogens invasion,removal of foreign heterogeneity,and protect the body′s safety.Modern research shows that tonic Chinese m...The immune system as an important defense system of the body,bear the resistance to foreign pathogens invasion,removal of foreign heterogeneity,and protect the body′s safety.Modern research shows that tonic Chinese medicine,including single herband compound formula,has the function of improving immune organ index,enhancing immune cellfunction and affecting the immune molecule production and secretion.This article will review the effects of traditional Chinese medicine on immune organs,immune cells and immune molecules,and provide reference for the clinical research of traditional Chinese medicine.展开更多
Objective To observe the expression of inlfammatory molecules in bone marrow immune cells of patients with immune-related hematocytopenia (IRH), and to investigate the immune mechanism and clinical signiifcance of the...Objective To observe the expression of inlfammatory molecules in bone marrow immune cells of patients with immune-related hematocytopenia (IRH), and to investigate the immune mechanism and clinical signiifcance of the disease. Methods Total of 36 IRH patients were selected as observation group and 30 healthy people were taken as control group. Serum cytokines levels, activity of immunocytes and expression of HLA-DR were detected. Immune lfuorescence was applied to observe the expression state of immunologic molecules and cytokines in IRH patients. Results Serum cytokines were elevated in various degrees in observation group. Compared with the control group, the cytokines levels were significantly higher (P < 0.05). After treatement with immunosuppressive drugs, the serum levels of cytokines in observation group reduced to a level close to the control group. HLA-DR were upregulated in activated tissue basophils, eosinophils, dendritic cells (DC) and macrophages of bone marrow in IRH patients, and POX activity in these immunocytes of IRH was higher than that of the control group. Immune molecules were highly expressed in eosinophils, DC and macrophages. Conclusions It is demonstrated that antibodies or self-reactive lymphocytes were produced in IRH marrow, which would cause lesions of hemocytes, and lead to pathological process ifnally. Structure of hematopoietic cells mutated and these cells might be acted as target cells of immunocytes in the pathological process. Immunocytes could secrete inlfammatory factors and lead to immunologic injury of hemocyte.展开更多
Objective Tumor-infiltrating immune cells and stromal cells in the tumor microenvironment(TME)significantly affect the prognosis of and immune response to lung adenocarcinoma(LUAD).In this study,we aimed to develop a ...Objective Tumor-infiltrating immune cells and stromal cells in the tumor microenvironment(TME)significantly affect the prognosis of and immune response to lung adenocarcinoma(LUAD).In this study,we aimed to develop a novel TME-related prognostic model based on immune and stromal genes in LUAD.Methods LUAD data from the TCGA database were used as the training cohort,and three Gene Expression Omnibus(GEO)datasets were used as the testing cohort.The Estimation of STromal and Immune cells in MAlignant Tumor tissues using Expression data algorithm was used to analyze the immune and stromal genes involved in the TME.Kaplan-Meier and Cox regression analyses were used to identify prognostic genes and construct a TME-related prognostic model.Gene set enrichment analysis and TIMER were used to analyze the immune features and signaling pathways of the model.Results A TME-related prognostic model based on six hub genes was generated that significantly stratified patients into the high-and low-risk groups in terms of overall survival.The model had strong predictive ability in both the training(TCGA)and testing(GEO)datasets and could serve as an independent prognostic factor for LUAD.Moreover,the low-risk group was characterized by greater immune cell infiltration and antitumor immune activity than the high-risk group.Importantly,the signature was closely associated with immune checkpoint molecules,which may serve as a predictor of patient response to immunotherapy.Finally,the hub genes BTK,CD28,INHA,PIK3CG,TLR4,and VEGFD were considered novel prognostic biomarkers for LUAD and were significantly correlated with immune cells.Conclusion The TME-related prognostic model could effectively predict the prognosis and reflect the TME status of LUAD.These six hub genes provided novel insights into the development of new therapeutic strategies.展开更多
Tissue-resident type 2 innate lymphoid cells(ILC2s)help orchestrate local inflammation.As early responding cells to danger signals and tissue damage,they produce key cytokines that directly influence the breadth and d...Tissue-resident type 2 innate lymphoid cells(ILC2s)help orchestrate local inflammation.As early responding cells to danger signals and tissue damage,they produce key cytokines that directly influence the breadth and depth of the immune response,including surveillance during tumor development and progression.Like T cells,ILC2s express immune checkpoint molecules on their surface that regulate their effector function.In lung cancer,Ciancaglini et al.展开更多
background Monoclonal antibodies(mAbs)targeting immune checkpoint molecules such as programmed death ligand 1(PD-L1),which is expressed in both immune and tumour cells,are conventional immunotherapy approaches.Althoug...background Monoclonal antibodies(mAbs)targeting immune checkpoint molecules such as programmed death ligand 1(PD-L1),which is expressed in both immune and tumour cells,are conventional immunotherapy approaches.Although approved as monotherapy for the first-line treatment of several cancers,mAbs targeting PD-L1 have shown limited efficacy in colorectal cancer(CRC).Here,we investigated if nucleic acids translated into anti-PD L1 nanobodies(PDL1Nbs)effectively suppress CRC tumourigenesis in mouse models.Methods Mice were transplanted with MC-38 mouse sporadic CRC(sCRC)cells or challenged with azoxymethane and dextran sodium sulfate,a combination treatment that induces colitis-associated CRC(CAC).The tumour-bearing mice were treated with a PDL1Nb-encoding plasmid DNA(pDNA)delivered via polymers,or treated with PDL1Nb-encoding nucleoside-modified messenger RNA(PDL1Nb mRNA)delivered via lipid nanoparticles(LNP).Moreover,bone marrow haematopoietic stem cells(BMHSCs)were differentiated and maturated by treating growth factors in the presence of PDL1Nb mRNA-LNP or control luciferase mRNA-LNP with/without lipopolysaccharide.We examined sCRC tumour proliferation and growth,CAC tumour incidences and numbers,tumour infiltration of immune cells and bone marrow-derived macrophages(BMDMs).results Polymer delivery of PDL1Nb pDNA efficiently repressed sCRC progression in tumour-bearing mice.Intriguingly,LNP delivery of the quadruple PDL1Nb(qPDL1Nb)mRNA showed a greater efficacy than the delivery of the monomeric PDL1Nb(mPDL1Nb)mRNA in suppressing sCRC tumour progression.Moreover,qPDL1Nb mRNA-LNP treatment significantly reduced CAC incidence.Mechanistically,PD-L1 blockade by qPDL1Nb resulted in marked decreases in tumour-infiltrating myeloid-derived suppressor cells and tumour-associated macrophages,as well as expression of PD-L1,but increases in tumour-infiltrating CD3+CD8+cells during CAC tumourigenesis.Notably,in vitro LNP delivery of PDL1Nb mRNA into BMHSCs significantly inhibited their differentiation and maturation into BMDMs and strikingly reduced the expression of PD-L1,CD80,CD86 and CD206 in BMDMs.展开更多
While the expression of programmed death ligand-1(PD-L1)is associated with response to immune therapy,PD-L1-negative patients may still benefit from immune treatment.Programmed death ligand-2(PD-L2),another crucial im...While the expression of programmed death ligand-1(PD-L1)is associated with response to immune therapy,PD-L1-negative patients may still benefit from immune treatment.Programmed death ligand-2(PD-L2),another crucial immune checkpoint molecule interacting with PD-1,correlates with the efficacy of various tumor immune therapies.This study investigates the expression of PD-L2 in non-small cell lung cancer(NSCLC)patients following anti-PD-1 therapy and its predictive value for clinical survival outcomes.Additionally,we explore the noninvasive,real-time,and dynamic quantitative analysis potential of PD-L2 positron emission tomography(PET)imaging in transplanted tumors.We utilized[^(68)Ga]Ga-labeled peptide HN11-1 for PD-L2 PET imaging.The results indicate a higher response rate to anti-PD-1 therapy in patients positive for both PD-L1 and PD-L2,with PD-L2 status independently predicting progression-free survival(PFS)with pembrolizumab treatment.Furthermore,[^(68)Ga]Ga-HN11-1 PET imaging demonstrates specificity in assessing PD-L2 status.Overall,we confirm the correlation between high PD-L2 expression and favorable PFS in NSCLC patients post anti-PD-1 therapy and highlight the promising potential of[^(68)Ga]Ga-HN11-1 as a specific tracer for PD-L2 in preclinical and initial human trials.展开更多
基金Supported by the National Key Sci-Tech Special Project of China,No.2018ZX10302207the Beijing Natural Science Foundation,No.7222191+3 种基金the Beijing Natural Science Foundation,No.7244426the Fundamental Research Funds for the Central Universities,Peking University,No.PKU2024XGK005the Peking University Medicine Seed Fund for Interdisciplinary Research,No.BMU2021MX007 and No.BMU2022MX001Fundamental Research Funds for the Central Universities,Peking University People’s Hospital Scientific Research Development Funds,No.RDY2020-06 and No.RDJ2022-14.
文摘Hepatocellular carcinoma(HCC)is a primary malignant tumor of the liver and one of the most common malignant tumors,as well as the third leading cause of cancer-related death.In recent years,immune checkpoint inhibitors have emerged as a key strategy in cancer treatment.However,anti-programmed cell death 1/programmed death ligand 1 therapies,one of the main immunotherapeutic approaches,only elicit a response in only approximately 20%of advanced HCC.This suggests that there may be other immune checkpoints playing important roles in HCC immunotherapy.Recent studies have highlighted Signal regulatory protein alpha(SIRPα)is a phagocytic checkpoint in macrophages and other immune cells,as a promising novel therapeutic target in tumor immunotherapy.This review summarizes current progress on SIRPαin HCC and identifies key challenges for future related research.
基金National Natural Science Foundation of China(No.81974577)。
文摘In recent years,immune checkpoint molecules have made breakthroughs in the fields of inducing graft tolerance,tumor immune escape and preventing autoimmunity.These immunoregulatory factors,when combined with ligand,can transduce the inhibitory signal into cells to negatively regulate the immune response,which brings new enlightenment for the immune research of pregnancy and pregnancy complications.In this review,we reviewed the immunomodulatory effects of CTLA-4,PD-1 and Tim-3 in pregnancy,in order to evaluate their potential effects in pregnancy,and to provide a new direction for the immunotherapy of pregnancy complications.
基金funded by the National Key Research and Development Project,grant number 2021YFE0192100Natural Science Foundation of Hunan Province,grant numbers 2021JJ30694,2023JJ30529+4 种基金Innovation and Entrepreneurship Training Program for College Students in Hunan Province,grant number S202210555254Key Projects of Hunan Provincial Education Department,grant number 21A0285Natural Science Foundation of Hunan Provincial and Municipal Co-Funding,grant number 2022JJ50029Key Projects of Shaoyang Science and Technology Bureau,grant number 2021GZ031Innovation and Entrepreneurship Training Program for College Students of the University of South China,grant numbers D202405212006326156,D202405210948392932,D202405211329047648,D202405221955420827.
文摘One of the most prevalent malignant tumors worldwide,stomach cancer still has a high incidence and fatality rate in China,and the number of young people developing early-onset gastric cancer is steadily increasing.The 5-year survival rate of stomach cancer is typically 30%–35%,the prognosis is bad,the patients’quality of life is low,and the progression of advanced gastric cancer cannot be effectively managed despite the use of surgical surgery,chemotherapy,and other medicines.We urgently need molecular biomarkers with high specificity and sensitivity to increase the early gastric cancer detection rate,extend patient survival,and improve patient quality of life.The initial diagnosis of gastric cancer primarily depends on gastroscopy and biopsy,and invasive procedures cause significant discomfort to patients.Similar to this,treating advanced and metastatic stomach cancer is a pressing issue that requires attention.More and more immune checkpoint molecules have been discovered,and corresponding inhibitors are gradually being applied to clinical diagnosis and treatment.Recently,some non-coding RNAs have begun to be used as new targets for the treatment of gastric cancer.Some non-coding RNAs are highly present in the serum or urine of gastric cancer patients and can be used as diagnostic markers or prognostic indicators.Many clinical trials targeting non-coding RNAs have also shown good therapeutic effects.In general,targeting non-coding RNAs has shown good therapeutic effects.The biomarkers for gastric cancer detection and treatment are reviewed in this article,focusing on the new non-coding RNAs used in diagnosis,prognosis,and treatment.Patients with stomach cancer should have access to more precise and efficient diagnosis and treatment choices as a result of ongoing technological advancements and thorough research.
基金supported by Jiangsu Commission of Health(No.x202308)The Suzhou Gusu Health Talents Scientific Research Project(No.GSWS2021052).
文摘To the editor:The liver’s immune-privileged status allows for a unique microenvironment that supports tumour growth and metastasis.In hepatocellular carcinoma(HCC),the balance between cytotoxic T lymphocytes and regulatory T cells plays a crucial role in determining patient outcomes.The expression of programmed cell death ligand 1(PD-1)and other immune checkpoint molecules contributes to a pro-tumourigenic microenvironment and is associated with poor prognosis.Additionally,the heterogeneity of the immune microenvironment adds complexity to disease progression and treatment response.
文摘AIM: To explore the effects of interferon-α(IFN-α) application on peripheral circulating CD1αdendritic cells (DCs) in patients with chronic hepatitis B, and the expression of HLA-DR, CD80, and ICAM-1 on CD1αDCs in order to explore the mechanism of immune modulation of IFN-α. METHODS: By flow cytometry technique, changes of CD1αDCs were monitored in 22 patients with chronic hepatitis B treated with IFN-αand in 16 such patients not treated with IFN-αwithin three months. Meanwhile, the expression of HLA-DR, CD80, and ICAM-1 on CD1αDCs was detected. RESULTS: In the group of IFN-αtreatment, the percentage of CD1αDCs in peripheral blood mono-nuclear cells was increased after three months of therapy. In patients who became negative for HBV-DNA after IFN-αtreatment, the increase of DCs was more prominent, while in control, these changes were not observed. Increased expression of HLA-DR, CD80, and ICAM-1 on CD1αDCs was also observed. CONCLUSION: CD1αDCs can be induced by IFN-αin vivo, and the immune related molecules such as HLA-DR, CD80, and ICAM-1 are up-regulated to some degree. This might be an important immune related mechanism of IFN-αtreatment for chronic hepatitis B.
基金supported by National Natural Science Foundation of China(81473549)National Natural Science Foundation of China Youth Fund Project(31402237)+1 种基金National "major New Drug Creation" Major Science and Technology Projects(2014ZX09304-306-04)Ministry of Education of the Central University Basic Scientific Research Business Fee(XDJK2015D016)
文摘The immune system as an important defense system of the body,bear the resistance to foreign pathogens invasion,removal of foreign heterogeneity,and protect the body′s safety.Modern research shows that tonic Chinese medicine,including single herband compound formula,has the function of improving immune organ index,enhancing immune cellfunction and affecting the immune molecule production and secretion.This article will review the effects of traditional Chinese medicine on immune organs,immune cells and immune molecules,and provide reference for the clinical research of traditional Chinese medicine.
文摘Objective To observe the expression of inlfammatory molecules in bone marrow immune cells of patients with immune-related hematocytopenia (IRH), and to investigate the immune mechanism and clinical signiifcance of the disease. Methods Total of 36 IRH patients were selected as observation group and 30 healthy people were taken as control group. Serum cytokines levels, activity of immunocytes and expression of HLA-DR were detected. Immune lfuorescence was applied to observe the expression state of immunologic molecules and cytokines in IRH patients. Results Serum cytokines were elevated in various degrees in observation group. Compared with the control group, the cytokines levels were significantly higher (P < 0.05). After treatement with immunosuppressive drugs, the serum levels of cytokines in observation group reduced to a level close to the control group. HLA-DR were upregulated in activated tissue basophils, eosinophils, dendritic cells (DC) and macrophages of bone marrow in IRH patients, and POX activity in these immunocytes of IRH was higher than that of the control group. Immune molecules were highly expressed in eosinophils, DC and macrophages. Conclusions It is demonstrated that antibodies or self-reactive lymphocytes were produced in IRH marrow, which would cause lesions of hemocytes, and lead to pathological process ifnally. Structure of hematopoietic cells mutated and these cells might be acted as target cells of immunocytes in the pathological process. Immunocytes could secrete inlfammatory factors and lead to immunologic injury of hemocyte.
基金Supported by grants from the National Natural Science Foundation of China(No.81772471 and 82172716).
文摘Objective Tumor-infiltrating immune cells and stromal cells in the tumor microenvironment(TME)significantly affect the prognosis of and immune response to lung adenocarcinoma(LUAD).In this study,we aimed to develop a novel TME-related prognostic model based on immune and stromal genes in LUAD.Methods LUAD data from the TCGA database were used as the training cohort,and three Gene Expression Omnibus(GEO)datasets were used as the testing cohort.The Estimation of STromal and Immune cells in MAlignant Tumor tissues using Expression data algorithm was used to analyze the immune and stromal genes involved in the TME.Kaplan-Meier and Cox regression analyses were used to identify prognostic genes and construct a TME-related prognostic model.Gene set enrichment analysis and TIMER were used to analyze the immune features and signaling pathways of the model.Results A TME-related prognostic model based on six hub genes was generated that significantly stratified patients into the high-and low-risk groups in terms of overall survival.The model had strong predictive ability in both the training(TCGA)and testing(GEO)datasets and could serve as an independent prognostic factor for LUAD.Moreover,the low-risk group was characterized by greater immune cell infiltration and antitumor immune activity than the high-risk group.Importantly,the signature was closely associated with immune checkpoint molecules,which may serve as a predictor of patient response to immunotherapy.Finally,the hub genes BTK,CD28,INHA,PIK3CG,TLR4,and VEGFD were considered novel prognostic biomarkers for LUAD and were significantly correlated with immune cells.Conclusion The TME-related prognostic model could effectively predict the prognosis and reflect the TME status of LUAD.These six hub genes provided novel insights into the development of new therapeutic strategies.
文摘Tissue-resident type 2 innate lymphoid cells(ILC2s)help orchestrate local inflammation.As early responding cells to danger signals and tissue damage,they produce key cytokines that directly influence the breadth and depth of the immune response,including surveillance during tumor development and progression.Like T cells,ILC2s express immune checkpoint molecules on their surface that regulate their effector function.In lung cancer,Ciancaglini et al.
基金supported by the IBR Pilot Awards(SM and W-MC)associated with the COBRE grant P30GM131944(W Steven Ward,PI)the Yao Family Professorship(W-MC)and the B.H.and Alice C.Beams Foundation(SM)and was partially supported by U01CA188387-01(WJ and W-MC)+3 种基金the Kosasa Foundation and the Office of the Vice President for Research at the University of Hawai’i(SM)The Pardi Laboratory was supported by the National Institute of Allergy and Infectious Diseases(NIAID,R01AI153064)The Experimental NeuroAcoustics and Biophysics Laboratory(ENABL,PA)was supported by the American Cancer Society’s grant IRG-18-160-16seed funds from the Department of Neurosurgery,University of Maryland School of Medicine,Baltimore,Maryland.
文摘background Monoclonal antibodies(mAbs)targeting immune checkpoint molecules such as programmed death ligand 1(PD-L1),which is expressed in both immune and tumour cells,are conventional immunotherapy approaches.Although approved as monotherapy for the first-line treatment of several cancers,mAbs targeting PD-L1 have shown limited efficacy in colorectal cancer(CRC).Here,we investigated if nucleic acids translated into anti-PD L1 nanobodies(PDL1Nbs)effectively suppress CRC tumourigenesis in mouse models.Methods Mice were transplanted with MC-38 mouse sporadic CRC(sCRC)cells or challenged with azoxymethane and dextran sodium sulfate,a combination treatment that induces colitis-associated CRC(CAC).The tumour-bearing mice were treated with a PDL1Nb-encoding plasmid DNA(pDNA)delivered via polymers,or treated with PDL1Nb-encoding nucleoside-modified messenger RNA(PDL1Nb mRNA)delivered via lipid nanoparticles(LNP).Moreover,bone marrow haematopoietic stem cells(BMHSCs)were differentiated and maturated by treating growth factors in the presence of PDL1Nb mRNA-LNP or control luciferase mRNA-LNP with/without lipopolysaccharide.We examined sCRC tumour proliferation and growth,CAC tumour incidences and numbers,tumour infiltration of immune cells and bone marrow-derived macrophages(BMDMs).results Polymer delivery of PDL1Nb pDNA efficiently repressed sCRC progression in tumour-bearing mice.Intriguingly,LNP delivery of the quadruple PDL1Nb(qPDL1Nb)mRNA showed a greater efficacy than the delivery of the monomeric PDL1Nb(mPDL1Nb)mRNA in suppressing sCRC tumour progression.Moreover,qPDL1Nb mRNA-LNP treatment significantly reduced CAC incidence.Mechanistically,PD-L1 blockade by qPDL1Nb resulted in marked decreases in tumour-infiltrating myeloid-derived suppressor cells and tumour-associated macrophages,as well as expression of PD-L1,but increases in tumour-infiltrating CD3+CD8+cells during CAC tumourigenesis.Notably,in vitro LNP delivery of PDL1Nb mRNA into BMHSCs significantly inhibited their differentiation and maturation into BMDMs and strikingly reduced the expression of PD-L1,CD80,CD86 and CD206 in BMDMs.
基金the National Natural Science Foundation of China(Grant numbers 91859207 and 81771873)the Science and Technology Innovation Team Talent Project of Hunan Province(Grant number 2021RC4056)+2 种基金the Natural Science Foundation of Hunan Province(Grant number 2023JJ30976)the National Natural Science Foundation of China(Grant number 82372003)the Postdoctoral Fellowship Program of CPSF(Grant number GZC20233586).
文摘While the expression of programmed death ligand-1(PD-L1)is associated with response to immune therapy,PD-L1-negative patients may still benefit from immune treatment.Programmed death ligand-2(PD-L2),another crucial immune checkpoint molecule interacting with PD-1,correlates with the efficacy of various tumor immune therapies.This study investigates the expression of PD-L2 in non-small cell lung cancer(NSCLC)patients following anti-PD-1 therapy and its predictive value for clinical survival outcomes.Additionally,we explore the noninvasive,real-time,and dynamic quantitative analysis potential of PD-L2 positron emission tomography(PET)imaging in transplanted tumors.We utilized[^(68)Ga]Ga-labeled peptide HN11-1 for PD-L2 PET imaging.The results indicate a higher response rate to anti-PD-1 therapy in patients positive for both PD-L1 and PD-L2,with PD-L2 status independently predicting progression-free survival(PFS)with pembrolizumab treatment.Furthermore,[^(68)Ga]Ga-HN11-1 PET imaging demonstrates specificity in assessing PD-L2 status.Overall,we confirm the correlation between high PD-L2 expression and favorable PFS in NSCLC patients post anti-PD-1 therapy and highlight the promising potential of[^(68)Ga]Ga-HN11-1 as a specific tracer for PD-L2 in preclinical and initial human trials.
