As one of the most common metastatic sites of malignancies,bone has a unique microenvironment that allows metastatic tumor cells to grow and flourish.The fenestrated capillaries in the bone,bone matrix,and bone cells,...As one of the most common metastatic sites of malignancies,bone has a unique microenvironment that allows metastatic tumor cells to grow and flourish.The fenestrated capillaries in the bone,bone matrix,and bone cells,including osteoblasts and osteoclasts,together maintain the homeostasis of the bone microenvironment.In contrast,tumor-derived factors act on bone components,leading to subsequent bone resorption or excessive bone formation.The various pathways involved also provide multiple targets for therapeutic strategies against bone metastases.In this review,we summarize the current understanding of the mechanism of bone metastases.Based on the general process of bone metastases,we specifically highlight the complex crosstalk between tumor cells and the bone microenvironment and the current management of cancer bone metastases.展开更多
Background:Radiotherapy(RT)is a key treatment modality in cancer therapy,utilizing high-energy radiation to directly kill tumor cells.Recent research has increasingly highlighted RT’s potential to indirectly enhance ...Background:Radiotherapy(RT)is a key treatment modality in cancer therapy,utilizing high-energy radiation to directly kill tumor cells.Recent research has increasingly highlighted RT’s potential to indirectly enhance antitumor immunity.However,this immune activation alone often fails to generate sustained systemic antitumor responses.In this study,we aimed to investigate the antitumor effects of combining cholesterolized toll-like receptor 7(TLR7)agonist liposomes,specifically 1V209-Cho-Lip,with RT.Methods:Mouse tumor models were used to assess the impact of combining 1V209-Cho-Lip with RT on tumor progression and modification of the tumor microenvironment.In vitro,primary mouse bone marrow-derived dendritic cells(BMDCs)were utilized to investigate changes in function and the activated pathways through RNA sequencing.Additionally,we explored the role of oxidized mitochondrial DNA(ox-mtDNA)released from irradiated tumor cells as a damage-associated molecular pattern in modulating immune responses.The involvement of interleukin-1β(IL-1β)and the inflammasome pathway in the antitumor efficacy of the combined treatment was evaluated using Il-1β^(−/−)and cysteinyl aspartate specific proteinase 1 knockout(Casp1^(−/−))mouse models.Results:The combination of 1V209-Cho-Lip and RT significantly inhibited tumor growth and induced antitumor immunity in tumor models.This combination therapy enhanced maturation,antigen presentation and IL-1βsecretion of dendritic cells(DCs)in vitro.Ox-mtDNA released from irradiated tumor cells synergized with 1V209-Cho-Lip to activate the inflammasome pathway in DCs.The antitumor effect of the combined therapy was significantly reduced in Il-1β^(−/−)and Casp1^(−/−)mice.Conclusions:This study suggests that the combination of 1V209-Cho-Lip with RT might be a promising antitumor strategy and further studies are warranted to explore the clinical relevance of this combination therapy.展开更多
Dietary fatty acids(FAs)are associated with the therapeutic intervention under various health conditions.Human γδ-T cells are indispensable for immunosurveillance toward malignant cells.However,their impact onγδ-T...Dietary fatty acids(FAs)are associated with the therapeutic intervention under various health conditions.Human γδ-T cells are indispensable for immunosurveillance toward malignant cells.However,their impact onγδ-T cell metabolism and function remains poorly unexplored.Here,we applied targeted metabolomics analysis to serum FAs among cancer patients undergoing γδ-T cell therapy and discovered that palmitic acid(PA)or oleic acid(OA)levels were associated with the efficacy of Vγ9Vδ2-T cell therapy.We further elucidated that PA suppresses the antitumor activity of Vγ9Vδ2-T cells by disrupting metabolic processes and inhibiting the secretion of lytic granules,whereas OA restores the impaired antitumor activity of Vγ9Vδ2-T cells.Mechanistically,we surprisingly found that PA stimulates Vγ9Vδ2-T cells to secrete excessive IFNγ,which in turn induces cell pyroptosis,ultimately resulting in decreased antitumor activity.展开更多
Epigenetic alternations concern heritable yet reversible changes in histone or DNA modifications that regulate gene activity beyond the underlying sequence.Epigenetic dysregulation is often linked to human disease,not...Epigenetic alternations concern heritable yet reversible changes in histone or DNA modifications that regulate gene activity beyond the underlying sequence.Epigenetic dysregulation is often linked to human disease,notably cancer.With the development of various drugs targeting epigenetic regulators,epigenetic-targeted therapy has been applied in the treatment of hematological malignancies and has exhibited viable therapeutic potential for solid tumors in preclinical and clinical trials.In this review,we summarize the aberrant functions of enzymes in DNA methylation,histone acetylation and histone methylation during tumor progression and highlight the development of inhibitors of or drugs targeted at epigenetic enzymes.展开更多
A significant proportion of non-small cell lung cancer(NSCLC) patients experience accumulating chemotherapy-related adverse events,motivating the design of chemosensitizating strategies.The main cytotoxic damage induc...A significant proportion of non-small cell lung cancer(NSCLC) patients experience accumulating chemotherapy-related adverse events,motivating the design of chemosensitizating strategies.The main cytotoxic damage induced by chemotherapeutic agents is DNA double-strand breaks(DSB).It is thus conceivable that DNA-dependent protein kinase(DNA-PK) inhibitors which attenuate DNA repair would enhance the anti-tumor effect of chemotherapy.The present study aims to systematically evaluate the efficacy and safety of a novel DNA-PK inhibitor M3814 in synergy with chemotherapies on NSCLC.We identified increased expression of DNA-PK in human NSCLC tissues which was associated with poor prognosis.M3814 potentiated the anti-tumor effect of paclitaxel and etoposide in A549,H460 and H1703 NSCLC cell lines.In the four combinations based on two NSCLC xenograft models and two chemotherapy,we also observed tumor regression at tolerated doses in vivo.Moreover,we identified a P53-dependent accelerated senescence response by M3814 following treatment with paclitaxel/etoposide.The present study provides a theoretical basis for the use of M3814 in combination with paclitaxel and etoposide in clinical practice,with hope to aid the optimization of NSCLC treatment.展开更多
The immunosuppressive tumor microenvironment(TME)is crucial in the occurrence of tumorigenesis,metastasis,and drug resistance.Among all stromal cells,tumor-associated macrophages(TAMs)are recognized as vital component...The immunosuppressive tumor microenvironment(TME)is crucial in the occurrence of tumorigenesis,metastasis,and drug resistance.Among all stromal cells,tumor-associated macrophages(TAMs)are recognized as vital components causing the TME to be favorable for cancer cells and are also main targets in cancer immunotherapy.To date,nanoparticle(NP)-based drug delivery systems,as new technology platforms,have exhibited considerable advantages,such as targeted drug delivery at tumor sites,enhanced drug transport efficiency,and controllable drug release profiles,which provide new approaches for cancer therapy.Regarding TAM-targeting nanoparticles,various therapeutic strategies have been developed by varying their design,namely,by blocking TAM recruitment,promoting TAM transformation,and directly diminishing existing TAMs.In the current review,we provide a brief overview of the role of TAMs in the tumor microenvironment and their functions and highlight strategies for TAM targeting.Moreover,the applications of nanoparticles in targeting TAMs to improve cancer therapeutic efficiency are summarized.展开更多
Early studies shed light on the immune suppression of immune checkpoint molecules in the cancer microenvironment,with later studies applying immune checkpoint blockade(ICB)in treatment of various malignancies.Despite ...Early studies shed light on the immune suppression of immune checkpoint molecules in the cancer microenvironment,with later studies applying immune checkpoint blockade(ICB)in treatment of various malignancies.Despite the encouraging efficacy of ICBs in a substantial subset of cancer patients,the treatment response varies.Gene mutations of both tumor cells and immune cells in the tumor microenvironment have recently been identified as potential predictors of the ICB response.Recent developments in gene expression profiling of tumors have allowed identification of a panel of mutated genes that may affect tumor cell response to ICB treatment.In this review,we discuss the association of the ICB response with gene expression and mutation profiles in tumor cells,which it is hoped will help to optimize the clinical application of ICBs in cancer patients.展开更多
In a recent study published in Nature Medicine,Yost et al.1 described the clonal replacement of tumor-specific T cells after treatment with PD-1 antibodies.This finding reveals the intrinsic ability of the tumor micro...In a recent study published in Nature Medicine,Yost et al.1 described the clonal replacement of tumor-specific T cells after treatment with PD-1 antibodies.This finding reveals the intrinsic ability of the tumor microenvironment to attract new T cells,which has crucial applications for the design of immune checkpoint blockade(ICB)therapies(Fig.1).Over the past few decades,ICB therapies have been successful in some patients with different types of cancer by blocking inhibitory checkpoint receptors on T cells,and thus restoring T cell-mediated immune responses as well as recruiting more T cells into the tumor environment.展开更多
Background Optimising the immunogenicity of COVID-19 vaccines to improve their protection against disease is necessary.Fractional dosing by intradermal(ID)administration has been shown to be equally immunogenic as int...Background Optimising the immunogenicity of COVID-19 vaccines to improve their protection against disease is necessary.Fractional dosing by intradermal(ID)administration has been shown to be equally immunogenic as intramuscular(IM)administration for several vaccines,but the immunogenicity of ID inactivated whole severe acute respiratory syndrome coronavirus 2(SARS-CoV-2)at the full dose is unknown.This study(NCT04800133)investigated the superiority of antibody and T-cell responses of full-dose CoronaVac by ID over IM administration in adolescents.Methods Participants aged 11–17 years received two doses of IM or ID vaccine,followed by the 3rd dose 13–42 days later.Humoral and cellular immunogenicity outcomes were measured post-dose 2(IM-CC versus ID-CC)and post-dose 3(IMCCC versus ID-CCC).Doses 2 and 3 were administered to 173 and 104 adolescents,respectively.Results Spike protein(S)immunoglobulin G(IgG),S-receptor-binding domain(RBD)IgG,S IgG Fcγreceptor IIIa(FcγRIIIa)-binding,SNM[sum of individual(S),nucleocapsid protein(N),and membrane protein(M)peptide pool]-specific interleukin-2(IL-2)+CD4^(+),SNM-specific IL-2^(+)CD8^(+),S-specific IL-2^(+)CD8^(+),N-specific IL-2^(+)CD4^(+),N-specific IL-2^(+)CD8^(+)and M-specific IL-2^(+)CD4^(+)responses fulfilled the superior and non-inferior criteria for ID-CC compared to IM-CC,whereas IgG avidity was inferior.For ID-CCC,S-RBD IgG,surrogate virus neutralisation test,90%plaque reduction neutralisation titre(PRNT90),PRNT50,S IgG avidity,S IgG FcγRIIIa-binding,M-specific IL-2^(+)CD4^(+),interferon-γ+CD8^(+)and IL-2^(+)CD8^(+)responses were superior and non-inferior to IM-CCC.The estimated vaccine efficacies were 49%,52%,66%and 79%for IM-CC,ID-CC,IM-CCC and ID-CCC,respectively.The ID groups reported more local,mild adverse reactions.Conclusion This is the first study to demonstrate superior antibody and M-specific T-cell responses by ID inactivated SARSCoV-2 vaccination and serves as the basis for future research to improve the immunogenicity of inactivated vaccines.展开更多
A recent study published in Cell by Tyler N.Starr et al. presented a quantitative deep mutational scanning platform that allowed for the characterization of potential amino acid(AA)mutations to the SARS-CoV-2 receptor...A recent study published in Cell by Tyler N.Starr et al. presented a quantitative deep mutational scanning platform that allowed for the characterization of potential amino acid(AA)mutations to the SARS-CoV-2 receptor binding domain(RBD).The mutationphenotype maps provided in this work determined the influence of RBD expression and binding affinity to human cell-surface protein angiotensin-converting enzyme 2(ACE2)induced by fully random substitution for each AA of RBD.This work identified pivotal positions for virus binding and entry into cells,facilitating the development of countermeasures for COVID-19,such as vaccines.展开更多
A recent study published in Nature by Combes et al.1 introduced a whole-blood-preserving single-cell analysis strategy to explore the contributions of the immune cells,including neutrophils,monocytes,platelets,and lym...A recent study published in Nature by Combes et al.1 introduced a whole-blood-preserving single-cell analysis strategy to explore the contributions of the immune cells,including neutrophils,monocytes,platelets,and lymphocytes.The team comprehensively analyzed a variety of cellular and serological immune features between severe and mild to moderate phenotypes of patients with coronavirus disease 2019(COVID-19),in order to identify potential targets of immunotherapies for the severe COVID-19 patients who need prompt and effective treatments.展开更多
In a recent study in Nature,Ishizuka et al.1 proposed a new strategy to restore sensitivity to immune checkpoint blockades(ICBs)through the loss of RNA-editing enzyme ADAR1(adenine deaminase acting on RNA 1).This find...In a recent study in Nature,Ishizuka et al.1 proposed a new strategy to restore sensitivity to immune checkpoint blockades(ICBs)through the loss of RNA-editing enzyme ADAR1(adenine deaminase acting on RNA 1).This finding identifies ADAR1 as an attractive target to improve the treatment response in ICB-resistant patient.展开更多
Cancer remains a major global health challenge,with conventional treatments like chemotherapy and radiotherapy often hindered by significant side effects,lack of specificity,and limited efficacy in advanced cases.Amon...Cancer remains a major global health challenge,with conventional treatments like chemotherapy and radiotherapy often hindered by significant side effects,lack of specificity,and limited efficacy in advanced cases.Among emerging therapeutic strategies,mRNA vaccines have shown remarkable potential due to their adaptability,rapid production,and capability for personalized cancer treatment.This review provides an in-depth analysis of messenger RNA(mRNA)vaccines as a therapeutic approach for cancer immunotherapy,focusing on their molecular biology,classification,mechanisms,and clinical studies.Derived from reported literature and data on clinicaltrials.gov,it examines studies on mRNA vaccines encoding tumor-specific antigens(TSAs),tumor-associated antigens(TAAs),immunomodulators,and chimeric antigen receptors(CARs)across various cancer types.The review highlights the ability of mRNA vaccines to encode TSAs and TAAs,enabling personalized cancer treatments,and classifies these vaccines into non-replicating and self-amplifying types.It further explores their mechanisms of action,including antigen presentation and immune activation,while emphasizing findings from clinical studies that demonstrate the potential of mRNA vaccines in cancer therapy.Despite their promise,challenges remain in enhancing delivery systems,improving immunogenicity,and addressing tumor heterogeneity.Overcoming these obstacles will require further investigation to fully harness the potential of mRNA vaccines in personalized cancer treatment.展开更多
基金This work is supported by the National Natural Science Foundation of China(reference number:81602492)the National Key Research and Development Program of China(reference number:2016YFA0201402)the National Major Scientific and Technological Special Project for"Significant New Drugs Development"(reference number:2018ZX09733001).
文摘As one of the most common metastatic sites of malignancies,bone has a unique microenvironment that allows metastatic tumor cells to grow and flourish.The fenestrated capillaries in the bone,bone matrix,and bone cells,including osteoblasts and osteoclasts,together maintain the homeostasis of the bone microenvironment.In contrast,tumor-derived factors act on bone components,leading to subsequent bone resorption or excessive bone formation.The various pathways involved also provide multiple targets for therapeutic strategies against bone metastases.In this review,we summarize the current understanding of the mechanism of bone metastases.Based on the general process of bone metastases,we specifically highlight the complex crosstalk between tumor cells and the bone microenvironment and the current management of cancer bone metastases.
基金supported by the National Science Foundation for Excellent Young Scholars(32122052)National Natural Science Foundation Regional Innovation and Development(No.U19A2003)+3 种基金National Natural Science Foundation of China(82102896)China Postdoctoral Science Foundation(2024M762248)Natural Science Foundation of Sichuan Province(2024NSFSC1883)Postdoctor Research Fund of West China Hospital,Sichuan University(2024HXBH055).
文摘Background:Radiotherapy(RT)is a key treatment modality in cancer therapy,utilizing high-energy radiation to directly kill tumor cells.Recent research has increasingly highlighted RT’s potential to indirectly enhance antitumor immunity.However,this immune activation alone often fails to generate sustained systemic antitumor responses.In this study,we aimed to investigate the antitumor effects of combining cholesterolized toll-like receptor 7(TLR7)agonist liposomes,specifically 1V209-Cho-Lip,with RT.Methods:Mouse tumor models were used to assess the impact of combining 1V209-Cho-Lip with RT on tumor progression and modification of the tumor microenvironment.In vitro,primary mouse bone marrow-derived dendritic cells(BMDCs)were utilized to investigate changes in function and the activated pathways through RNA sequencing.Additionally,we explored the role of oxidized mitochondrial DNA(ox-mtDNA)released from irradiated tumor cells as a damage-associated molecular pattern in modulating immune responses.The involvement of interleukin-1β(IL-1β)and the inflammasome pathway in the antitumor efficacy of the combined treatment was evaluated using Il-1β^(−/−)and cysteinyl aspartate specific proteinase 1 knockout(Casp1^(−/−))mouse models.Results:The combination of 1V209-Cho-Lip and RT significantly inhibited tumor growth and induced antitumor immunity in tumor models.This combination therapy enhanced maturation,antigen presentation and IL-1βsecretion of dendritic cells(DCs)in vitro.Ox-mtDNA released from irradiated tumor cells synergized with 1V209-Cho-Lip to activate the inflammasome pathway in DCs.The antitumor effect of the combined therapy was significantly reduced in Il-1β^(−/−)and Casp1^(−/−)mice.Conclusions:This study suggests that the combination of 1V209-Cho-Lip with RT might be a promising antitumor strategy and further studies are warranted to explore the clinical relevance of this combination therapy.
基金supported in part by the General Research Fund(17122519,17126317,1712222217119123,17106624)+5 种基金the Collaborative Research Fund(C4008-23W)Research Grants Council of Hong Kongthe Health and Medical Research Fund,Food and Health Bureau(18192021)Hong Kong SAR GovernmentSeed Funding for Strategic Interdisciplinary Research Scheme,University of Hong Kong Hong Kong SAR,ChinaShenzhen Institute of Synthetic Biology Scientific Research Program(ZTXM20214004),Shenzhen,China.
文摘Dietary fatty acids(FAs)are associated with the therapeutic intervention under various health conditions.Human γδ-T cells are indispensable for immunosurveillance toward malignant cells.However,their impact onγδ-T cell metabolism and function remains poorly unexplored.Here,we applied targeted metabolomics analysis to serum FAs among cancer patients undergoing γδ-T cell therapy and discovered that palmitic acid(PA)or oleic acid(OA)levels were associated with the efficacy of Vγ9Vδ2-T cell therapy.We further elucidated that PA suppresses the antitumor activity of Vγ9Vδ2-T cells by disrupting metabolic processes and inhibiting the secretion of lytic granules,whereas OA restores the impaired antitumor activity of Vγ9Vδ2-T cells.Mechanistically,we surprisingly found that PA stimulates Vγ9Vδ2-T cells to secrete excessive IFNγ,which in turn induces cell pyroptosis,ultimately resulting in decreased antitumor activity.
基金This work is supported by the Excellent Youth Foundation of Sichuan Scientific Committee Grant in China(No.2019JDJQ0008)the National Major Scientific and Technological Special Project for“Significant New Drugs Development”of China(No.2018ZX09733001)the National Key Research and Development Program of China(No.2016YFA0201402).
文摘Epigenetic alternations concern heritable yet reversible changes in histone or DNA modifications that regulate gene activity beyond the underlying sequence.Epigenetic dysregulation is often linked to human disease,notably cancer.With the development of various drugs targeting epigenetic regulators,epigenetic-targeted therapy has been applied in the treatment of hematological malignancies and has exhibited viable therapeutic potential for solid tumors in preclinical and clinical trials.In this review,we summarize the aberrant functions of enzymes in DNA methylation,histone acetylation and histone methylation during tumor progression and highlight the development of inhibitors of or drugs targeted at epigenetic enzymes.
基金supported by the National Natural Science Foundation Regional Innovation and Development (U19A2003, China)by the Excellent Youth Foundation of Sichuan Scientific Committee Grant in China (No. 2019JDJQ008)。
文摘A significant proportion of non-small cell lung cancer(NSCLC) patients experience accumulating chemotherapy-related adverse events,motivating the design of chemosensitizating strategies.The main cytotoxic damage induced by chemotherapeutic agents is DNA double-strand breaks(DSB).It is thus conceivable that DNA-dependent protein kinase(DNA-PK) inhibitors which attenuate DNA repair would enhance the anti-tumor effect of chemotherapy.The present study aims to systematically evaluate the efficacy and safety of a novel DNA-PK inhibitor M3814 in synergy with chemotherapies on NSCLC.We identified increased expression of DNA-PK in human NSCLC tissues which was associated with poor prognosis.M3814 potentiated the anti-tumor effect of paclitaxel and etoposide in A549,H460 and H1703 NSCLC cell lines.In the four combinations based on two NSCLC xenograft models and two chemotherapy,we also observed tumor regression at tolerated doses in vivo.Moreover,we identified a P53-dependent accelerated senescence response by M3814 following treatment with paclitaxel/etoposide.The present study provides a theoretical basis for the use of M3814 in combination with paclitaxel and etoposide in clinical practice,with hope to aid the optimization of NSCLC treatment.
基金the Excellent Youth Foundation of the Sichuan Scientific Committee Grant in China(No.2019JDJQ008)the National Natural Science Foundation for Regional Innovation and Development(No.U19A2003).
文摘The immunosuppressive tumor microenvironment(TME)is crucial in the occurrence of tumorigenesis,metastasis,and drug resistance.Among all stromal cells,tumor-associated macrophages(TAMs)are recognized as vital components causing the TME to be favorable for cancer cells and are also main targets in cancer immunotherapy.To date,nanoparticle(NP)-based drug delivery systems,as new technology platforms,have exhibited considerable advantages,such as targeted drug delivery at tumor sites,enhanced drug transport efficiency,and controllable drug release profiles,which provide new approaches for cancer therapy.Regarding TAM-targeting nanoparticles,various therapeutic strategies have been developed by varying their design,namely,by blocking TAM recruitment,promoting TAM transformation,and directly diminishing existing TAMs.In the current review,we provide a brief overview of the role of TAMs in the tumor microenvironment and their functions and highlight strategies for TAM targeting.Moreover,the applications of nanoparticles in targeting TAMs to improve cancer therapeutic efficiency are summarized.
基金This work is supported by the National Natural Science Foundation of China(No.81602492)the National Key Research and Development Program of China(No.2016YFA0201402).
文摘Early studies shed light on the immune suppression of immune checkpoint molecules in the cancer microenvironment,with later studies applying immune checkpoint blockade(ICB)in treatment of various malignancies.Despite the encouraging efficacy of ICBs in a substantial subset of cancer patients,the treatment response varies.Gene mutations of both tumor cells and immune cells in the tumor microenvironment have recently been identified as potential predictors of the ICB response.Recent developments in gene expression profiling of tumors have allowed identification of a panel of mutated genes that may affect tumor cell response to ICB treatment.In this review,we discuss the association of the ICB response with gene expression and mutation profiles in tumor cells,which it is hoped will help to optimize the clinical application of ICBs in cancer patients.
基金This work was supported by the National Major Scientific and Technological Special Project for“Significant New Drugs Development”(No.2018ZX09733001).
文摘In a recent study published in Nature Medicine,Yost et al.1 described the clonal replacement of tumor-specific T cells after treatment with PD-1 antibodies.This finding reveals the intrinsic ability of the tumor microenvironment to attract new T cells,which has crucial applications for the design of immune checkpoint blockade(ICB)therapies(Fig.1).Over the past few decades,ICB therapies have been successful in some patients with different types of cancer by blocking inhibitory checkpoint receptors on T cells,and thus restoring T cell-mediated immune responses as well as recruiting more T cells into the tumor environment.
基金the research grants COVID19F12,COVID19F10 and COVID19F02 awarded to LYL by the Health Bureau of the Government of Hong Kong,whilst TIYS was partly supported by a donation in memory of Ton Lung Quong and Reverend Marion QuongThe research work was supported additionally by grants from the Health and Medical Research Fund Commissioned Research on the Novel Coronavirus Disease(COVID-19)+1 种基金Hong Kong SAR(COVID190115)and the Theme-based Research Scheme of the Research Grants Council of the Hong Kong Special Administrative Region,China(T11-712/19-N and T11-705/21-N)The funding sources were not involved in the study design,data collection,laboratory assays,statistical computation,interpretation,or final conclusions of this project.
文摘Background Optimising the immunogenicity of COVID-19 vaccines to improve their protection against disease is necessary.Fractional dosing by intradermal(ID)administration has been shown to be equally immunogenic as intramuscular(IM)administration for several vaccines,but the immunogenicity of ID inactivated whole severe acute respiratory syndrome coronavirus 2(SARS-CoV-2)at the full dose is unknown.This study(NCT04800133)investigated the superiority of antibody and T-cell responses of full-dose CoronaVac by ID over IM administration in adolescents.Methods Participants aged 11–17 years received two doses of IM or ID vaccine,followed by the 3rd dose 13–42 days later.Humoral and cellular immunogenicity outcomes were measured post-dose 2(IM-CC versus ID-CC)and post-dose 3(IMCCC versus ID-CCC).Doses 2 and 3 were administered to 173 and 104 adolescents,respectively.Results Spike protein(S)immunoglobulin G(IgG),S-receptor-binding domain(RBD)IgG,S IgG Fcγreceptor IIIa(FcγRIIIa)-binding,SNM[sum of individual(S),nucleocapsid protein(N),and membrane protein(M)peptide pool]-specific interleukin-2(IL-2)+CD4^(+),SNM-specific IL-2^(+)CD8^(+),S-specific IL-2^(+)CD8^(+),N-specific IL-2^(+)CD4^(+),N-specific IL-2^(+)CD8^(+)and M-specific IL-2^(+)CD4^(+)responses fulfilled the superior and non-inferior criteria for ID-CC compared to IM-CC,whereas IgG avidity was inferior.For ID-CCC,S-RBD IgG,surrogate virus neutralisation test,90%plaque reduction neutralisation titre(PRNT90),PRNT50,S IgG avidity,S IgG FcγRIIIa-binding,M-specific IL-2^(+)CD4^(+),interferon-γ+CD8^(+)and IL-2^(+)CD8^(+)responses were superior and non-inferior to IM-CCC.The estimated vaccine efficacies were 49%,52%,66%and 79%for IM-CC,ID-CC,IM-CCC and ID-CCC,respectively.The ID groups reported more local,mild adverse reactions.Conclusion This is the first study to demonstrate superior antibody and M-specific T-cell responses by ID inactivated SARSCoV-2 vaccination and serves as the basis for future research to improve the immunogenicity of inactivated vaccines.
基金This work was supported by the National Key Research and Development Program of China(2020YFC0860200)the Key Research and Development Program of Sichuan Province(2020YFS0008).
文摘A recent study published in Cell by Tyler N.Starr et al. presented a quantitative deep mutational scanning platform that allowed for the characterization of potential amino acid(AA)mutations to the SARS-CoV-2 receptor binding domain(RBD).The mutationphenotype maps provided in this work determined the influence of RBD expression and binding affinity to human cell-surface protein angiotensin-converting enzyme 2(ACE2)induced by fully random substitution for each AA of RBD.This work identified pivotal positions for virus binding and entry into cells,facilitating the development of countermeasures for COVID-19,such as vaccines.
文摘A recent study published in Nature by Combes et al.1 introduced a whole-blood-preserving single-cell analysis strategy to explore the contributions of the immune cells,including neutrophils,monocytes,platelets,and lymphocytes.The team comprehensively analyzed a variety of cellular and serological immune features between severe and mild to moderate phenotypes of patients with coronavirus disease 2019(COVID-19),in order to identify potential targets of immunotherapies for the severe COVID-19 patients who need prompt and effective treatments.
基金This work is supported by the National Major Scientific and Technological Special Project for“Significant New Drugs Development”(No.2018ZX09733001).
文摘In a recent study in Nature,Ishizuka et al.1 proposed a new strategy to restore sensitivity to immune checkpoint blockades(ICBs)through the loss of RNA-editing enzyme ADAR1(adenine deaminase acting on RNA 1).This finding identifies ADAR1 as an attractive target to improve the treatment response in ICB-resistant patient.
基金supported by grants from the 1.3.5 project for disciplines of excellence from West China Hospital of Sichuan University(No.ZYGD23038)the National Science Foundation for Excellent Young Scholars(No.32122052)+2 种基金the project fund for the development of a clinical evaluation technology platform for novel corona-virus vaccines and the research and development of a new preventive nasal spray coronavirus vaccine,the Young Scientists Fund of the National Natural Science Foundation of China(No.32401268)the Postdoctoral Fellowship Program of CPSF(No.GZB20240500)Sichuan Science and Technology Program(No.2024NSFSC1200).
文摘Cancer remains a major global health challenge,with conventional treatments like chemotherapy and radiotherapy often hindered by significant side effects,lack of specificity,and limited efficacy in advanced cases.Among emerging therapeutic strategies,mRNA vaccines have shown remarkable potential due to their adaptability,rapid production,and capability for personalized cancer treatment.This review provides an in-depth analysis of messenger RNA(mRNA)vaccines as a therapeutic approach for cancer immunotherapy,focusing on their molecular biology,classification,mechanisms,and clinical studies.Derived from reported literature and data on clinicaltrials.gov,it examines studies on mRNA vaccines encoding tumor-specific antigens(TSAs),tumor-associated antigens(TAAs),immunomodulators,and chimeric antigen receptors(CARs)across various cancer types.The review highlights the ability of mRNA vaccines to encode TSAs and TAAs,enabling personalized cancer treatments,and classifies these vaccines into non-replicating and self-amplifying types.It further explores their mechanisms of action,including antigen presentation and immune activation,while emphasizing findings from clinical studies that demonstrate the potential of mRNA vaccines in cancer therapy.Despite their promise,challenges remain in enhancing delivery systems,improving immunogenicity,and addressing tumor heterogeneity.Overcoming these obstacles will require further investigation to fully harness the potential of mRNA vaccines in personalized cancer treatment.
