Lynch syndrome(LS)is the most common hereditary colorectal cancer(CRC)predisposition syndrome,characterized by a high mutational burden and microsatellite instability-high(MSI-H)tumors.Immunology of LS-associated CRC(...Lynch syndrome(LS)is the most common hereditary colorectal cancer(CRC)predisposition syndrome,characterized by a high mutational burden and microsatellite instability-high(MSI-H)tumors.Immunology of LS-associated CRC(LS-CRC)is unique,with significant implications for treatment.Despite well-established knowledge of LS immunology,immunotherapy dose and treatment response can vary significantly based on local tumor immunity and specific germline pathogenic variant of LS genes.This variability necessitates tailored surveillance strategies and new personalised immunotherapy approaches for LS patients.LS-CRC often benefits from immunotherapy due to the distinct tumor microenvironment(TME)and the variety of tumor infiltrating lymphocytes(TILs).This perspective discusses a novel approach of analysing spatial TILs at a single-cell level using tumor whole slide images(WSIs)that accounts for the distinct TME of LS-CRC.By emphasizing the necessity of personalized medicine in hereditary cancer syndromes,the future research and clinical practices that enhance patient outcomes through precision oncology is inspired.展开更多
While chemo-immunotherapy has been established as the frontline therapeutic regimen for extensive-stage small cell lung cancer(ES-SCLC),durable responses persist predominantly in a minor population of patients.This un...While chemo-immunotherapy has been established as the frontline therapeutic regimen for extensive-stage small cell lung cancer(ES-SCLC),durable responses persist predominantly in a minor population of patients.This underscores critical need to elucidate underlying local tumor microenvironment and systematic immune profles for biomarker discovery.In this phase ll trial(ChiCTR2000038354),the efficacy,safety,and immune-genomic signatures of sintilimab(anti-PD-1 antibody)synergized with chemotherapy as first-line regimen for ES-SCLC were evaluated.The regimen demonstrated a median progression-free survival(PFS)of 6.9 months and median overall survival of 17.1 months,accompanied by a 12-month PFS rate of 16.9%,fulflling the primary endpoint.Manageable grade 3 or 4 treatment-related adverse events developed in 27.3%(12/44)of patients.The exploratory study indicated a higher infiltration of CD4^(+)/CD8^(+)CXCR5^(+)T follicle helper cell,CD8^(+)CD103^(+)tissue-resident memory T cells,and B cells in tumor tissue,associated with better response and prognosis.The study also indicated the presence of tumor macrophages(CD68^(+)CD163^(+)CSF1R^(+)SIGLEC5^(+))associated with immunotherapy resistance.Higher levels of monocyte-dendritic cells in pre-treatment peripheral blood mononuclear cells were found in durable clinical benefit group.Also,higher CD83,CD244,IL-12,and CD70,which are hallmarks of dendritic cells and activated T cells,were discovered by plasma proteomics to be connected with enhanced outcomes,while chemoattractant of macrophage,CSF-1,CCL3,CCL4,and IL-8,were found to predict a worse prognosis.Furthermore,a multimodal model was constructed and validated for stratifying ES-SCLC into high or low risk to predict the immunotherapy efficacy.This study sheds light on harnessing local and systematic immune profiles to better stratify patients with ES-SCLC for immunotherapy and putative combinational treatment.展开更多
BACKGROUND The coronavirus disease 2019(COVID-19)pandemic has been linked to an increased incidence of diabetes and diabetic ketoacidosis(DKA).However,the relationship between COVID-19 infection and progression to typ...BACKGROUND The coronavirus disease 2019(COVID-19)pandemic has been linked to an increased incidence of diabetes and diabetic ketoacidosis(DKA).However,the relationship between COVID-19 infection and progression to type 1 diabetes(T1D)in children has not been well defined.AIM To evaluate the influence of COVID-19 infection and inactivated vaccine adminis-tration on the progression of T1D among Chinese children.METHODS A total of 197 newly diagnosed patients with T1D were retrospectively enrolled from Children's Hospital of Fudan University between September 2020 and December 2023.The patients were divided into three groups based on their history of COVID-19 infection and vaccination:the infection group,the vacci-nation-only group,and the non-infection/non-vaccination group.Comprehensive clinical assessments and detailed immunological evaluations were performed to delineate the characteristics and immune responses of these groups.RESULTS The incidence of DKA was significantly higher in the COVID-19 infection group(70.2%)compared to the non-infection/non-vaccination group(62.5%)and vac-scination-only group(45.6%;P=0.015).Prior COVID-19 infection was correlated with increased DKA risk(OR:1.981,95%CI:1.026-3.825,P=0.042),while vacci-nation was associated with a reduced risk(OR:0.558,95%CI:0.312-0.998,P=0.049).COVID-19 infection mildly altered immune profiles,with modest dif-ferences in autoantibody positivity,lymphocyte distribution,and immunoglobulin levels.Notably,HLA-DR3 po-sitive children with a history of COVID-19 infection had an earlier T1D onset and lower fasting C-peptide levels than the HLA-DR3 negative children with a history of infection(both P<0.05).CONCLUSION COVID-19 infection predisposes children to severe T1D,characterized by enhanced DKA risk.Inactivated vaccination significantly lowers DKA incidence at T1D onset.These findings are valuable for guiding future vaccination and T1D risk surveillance strategies in epidemic scenarios in the general pediatric population.展开更多
Objective To review the senescent remodeling of the immune system with aging and its relevance to the increased susceptibility of the elderly to infectious diseases, along with an outlook on emerging immunological bio...Objective To review the senescent remodeling of the immune system with aging and its relevance to the increased susceptibility of the elderly to infectious diseases, along with an outlook on emerging immunological biomarkers. Data sources The data selected were from PubMed with relevant published articles in English or French from 1995 to the present. Searches were made using the terms immunosenescence and aging paired with the following： innate immunity, T-celr, B-cell, adaptive immunity and biomarkers. Articles were reviewed for additional citations and some information was gathered from web searches. Study selection Articles on aging of both the innate and adaptive immunity were reviewed, with special attention to the remodeling effect on the ability of the immune system to fight infectious diseases. Articles related to biomarkers of immunosenescence were selected with the goal of identifying immunological biomarkers predisposing the elderly to infections. Results Innate immunity is generally thought to be relatively well preserved or enhanced during aging compared with adaptive immunity which manifests more profound alterations. However, evidence, particularly in the last decade, reveals that both limbs of the immune system undergo profound remodeling with aging. Reported data on adaptive immunity is consistent and changes are well established but conflicting results about innate immunity were reported between in vivo and in vitro studies, as well as between murine and human studies. Epidemiological data suggests increased predisposition of the elderly to infections, but no compelling scientific evidence has directly linked senescent immune remodeling to this increased susceptibility. Recently, growing interest in identifying immunological biomarkers and defining immune risk phenotypes/profiles （IRP） has been expressed. Identification of biomarkers is in its early days and few potential biomarkers have been identified, with the Swedish having defined one IRP based on the adaptive immune response. Conclusions Aging does not necessarily lead to an unavoidable decline in immune functions. Instead, a complex remodeling occurs. Despite the lack of compelling scientific evidence, senescent immune remodeling surely is a significant contributing factor to the increased risk and severity of infections in the elderly. Although, no immunological biomarker has been formally linked to the increased risk of infections in the elderly, biomarkers remain a promising tool to predict the likelihood of healthy aging, the level of immune competence, and mortality risk in the elderly. Hence, more research is required to define healthy aging and identify immunological biomarkers.展开更多
文摘Lynch syndrome(LS)is the most common hereditary colorectal cancer(CRC)predisposition syndrome,characterized by a high mutational burden and microsatellite instability-high(MSI-H)tumors.Immunology of LS-associated CRC(LS-CRC)is unique,with significant implications for treatment.Despite well-established knowledge of LS immunology,immunotherapy dose and treatment response can vary significantly based on local tumor immunity and specific germline pathogenic variant of LS genes.This variability necessitates tailored surveillance strategies and new personalised immunotherapy approaches for LS patients.LS-CRC often benefits from immunotherapy due to the distinct tumor microenvironment(TME)and the variety of tumor infiltrating lymphocytes(TILs).This perspective discusses a novel approach of analysing spatial TILs at a single-cell level using tumor whole slide images(WSIs)that accounts for the distinct TME of LS-CRC.By emphasizing the necessity of personalized medicine in hereditary cancer syndromes,the future research and clinical practices that enhance patient outcomes through precision oncology is inspired.
基金funded by the Clinical Research Foundation of Shanghai Pulmonary Hospital(FKLY20013)National Key R&D Program of China(grant number 2023YFC2508604,2023YFC2508605)+2 种基金Tongji University Medicine-X Interdisciplinary Research Initiative(2025-0554-ZD-08)"Young Eagle Soaring"Talent Project of Shanghai Pulmonary Hospital(Fkcy2408)Innovent Biologics,Inc and Amoy Diagnostics Co.,Ltd.The IRB of Shanghai Pulmonary Hospital(L20-411-1)approved the protocol,all patients provided written informed consent.
文摘While chemo-immunotherapy has been established as the frontline therapeutic regimen for extensive-stage small cell lung cancer(ES-SCLC),durable responses persist predominantly in a minor population of patients.This underscores critical need to elucidate underlying local tumor microenvironment and systematic immune profles for biomarker discovery.In this phase ll trial(ChiCTR2000038354),the efficacy,safety,and immune-genomic signatures of sintilimab(anti-PD-1 antibody)synergized with chemotherapy as first-line regimen for ES-SCLC were evaluated.The regimen demonstrated a median progression-free survival(PFS)of 6.9 months and median overall survival of 17.1 months,accompanied by a 12-month PFS rate of 16.9%,fulflling the primary endpoint.Manageable grade 3 or 4 treatment-related adverse events developed in 27.3%(12/44)of patients.The exploratory study indicated a higher infiltration of CD4^(+)/CD8^(+)CXCR5^(+)T follicle helper cell,CD8^(+)CD103^(+)tissue-resident memory T cells,and B cells in tumor tissue,associated with better response and prognosis.The study also indicated the presence of tumor macrophages(CD68^(+)CD163^(+)CSF1R^(+)SIGLEC5^(+))associated with immunotherapy resistance.Higher levels of monocyte-dendritic cells in pre-treatment peripheral blood mononuclear cells were found in durable clinical benefit group.Also,higher CD83,CD244,IL-12,and CD70,which are hallmarks of dendritic cells and activated T cells,were discovered by plasma proteomics to be connected with enhanced outcomes,while chemoattractant of macrophage,CSF-1,CCL3,CCL4,and IL-8,were found to predict a worse prognosis.Furthermore,a multimodal model was constructed and validated for stratifying ES-SCLC into high or low risk to predict the immunotherapy efficacy.This study sheds light on harnessing local and systematic immune profiles to better stratify patients with ES-SCLC for immunotherapy and putative combinational treatment.
基金Supported by National Key Research and Development Program of China,No.2021YFC2701900 and No.2016YFC1305300.
文摘BACKGROUND The coronavirus disease 2019(COVID-19)pandemic has been linked to an increased incidence of diabetes and diabetic ketoacidosis(DKA).However,the relationship between COVID-19 infection and progression to type 1 diabetes(T1D)in children has not been well defined.AIM To evaluate the influence of COVID-19 infection and inactivated vaccine adminis-tration on the progression of T1D among Chinese children.METHODS A total of 197 newly diagnosed patients with T1D were retrospectively enrolled from Children's Hospital of Fudan University between September 2020 and December 2023.The patients were divided into three groups based on their history of COVID-19 infection and vaccination:the infection group,the vacci-nation-only group,and the non-infection/non-vaccination group.Comprehensive clinical assessments and detailed immunological evaluations were performed to delineate the characteristics and immune responses of these groups.RESULTS The incidence of DKA was significantly higher in the COVID-19 infection group(70.2%)compared to the non-infection/non-vaccination group(62.5%)and vac-scination-only group(45.6%;P=0.015).Prior COVID-19 infection was correlated with increased DKA risk(OR:1.981,95%CI:1.026-3.825,P=0.042),while vacci-nation was associated with a reduced risk(OR:0.558,95%CI:0.312-0.998,P=0.049).COVID-19 infection mildly altered immune profiles,with modest dif-ferences in autoantibody positivity,lymphocyte distribution,and immunoglobulin levels.Notably,HLA-DR3 po-sitive children with a history of COVID-19 infection had an earlier T1D onset and lower fasting C-peptide levels than the HLA-DR3 negative children with a history of infection(both P<0.05).CONCLUSION COVID-19 infection predisposes children to severe T1D,characterized by enhanced DKA risk.Inactivated vaccination significantly lowers DKA incidence at T1D onset.These findings are valuable for guiding future vaccination and T1D risk surveillance strategies in epidemic scenarios in the general pediatric population.
文摘Objective To review the senescent remodeling of the immune system with aging and its relevance to the increased susceptibility of the elderly to infectious diseases, along with an outlook on emerging immunological biomarkers. Data sources The data selected were from PubMed with relevant published articles in English or French from 1995 to the present. Searches were made using the terms immunosenescence and aging paired with the following： innate immunity, T-celr, B-cell, adaptive immunity and biomarkers. Articles were reviewed for additional citations and some information was gathered from web searches. Study selection Articles on aging of both the innate and adaptive immunity were reviewed, with special attention to the remodeling effect on the ability of the immune system to fight infectious diseases. Articles related to biomarkers of immunosenescence were selected with the goal of identifying immunological biomarkers predisposing the elderly to infections. Results Innate immunity is generally thought to be relatively well preserved or enhanced during aging compared with adaptive immunity which manifests more profound alterations. However, evidence, particularly in the last decade, reveals that both limbs of the immune system undergo profound remodeling with aging. Reported data on adaptive immunity is consistent and changes are well established but conflicting results about innate immunity were reported between in vivo and in vitro studies, as well as between murine and human studies. Epidemiological data suggests increased predisposition of the elderly to infections, but no compelling scientific evidence has directly linked senescent immune remodeling to this increased susceptibility. Recently, growing interest in identifying immunological biomarkers and defining immune risk phenotypes/profiles （IRP） has been expressed. Identification of biomarkers is in its early days and few potential biomarkers have been identified, with the Swedish having defined one IRP based on the adaptive immune response. Conclusions Aging does not necessarily lead to an unavoidable decline in immune functions. Instead, a complex remodeling occurs. Despite the lack of compelling scientific evidence, senescent immune remodeling surely is a significant contributing factor to the increased risk and severity of infections in the elderly. Although, no immunological biomarker has been formally linked to the increased risk of infections in the elderly, biomarkers remain a promising tool to predict the likelihood of healthy aging, the level of immune competence, and mortality risk in the elderly. Hence, more research is required to define healthy aging and identify immunological biomarkers.
