1 MHC-I Loss in the Immune Evasion of Cancer Cells Pancreatic ductal adenocarcinoma(PDAC)is a lethal cancer with a poor prognosis due to its aggressive nature and late detection.Recently,new discoveries in PDAC demons...1 MHC-I Loss in the Immune Evasion of Cancer Cells Pancreatic ductal adenocarcinoma(PDAC)is a lethal cancer with a poor prognosis due to its aggressive nature and late detection.Recently,new discoveries in PDAC demonstrated receptor-interacting protein kinase 2(RIPK2)triggering immune evasion.Mechanistically,RIPK2 drives the desmoplastic tumor microenvironment(TME)and restricts the activation and density of tumor-infiltrating effector T cells by impairing the expression of major histocompatibility complex class I(MHC-I)[1].This process might be relevant in different solid cancer entities as illustrated by analyzing publicly available databases.展开更多
Introduction: The immunity against cervical cancers is many unknown. Major histocompatability complex class I (MHC-I) with the alpha domain has binding site for Cytotoxic T cells (CD8+) to target cells. The objective ...Introduction: The immunity against cervical cancers is many unknown. Major histocompatability complex class I (MHC-I) with the alpha domain has binding site for Cytotoxic T cells (CD8+) to target cells. The objective of this experiment is to know the expression of CD8+ and MHC-I in cervical cancer with HPV infection. Method: DNA was isolated from seventeen sample cervical cancer tissues frozen section. Diagnose related with HPV was made by PCR. Paraffin block of the tissues was cut in thoroughly cleaned cryotome and place in glass plate that covered with poly-elysine. The immuno-histochemistry is done with monoclonal antibody again MHC-I and CD8+ with TSA-indirect method. The power of expression was counted the number of positive cells to express the MHC-I and CD8+ every 100 cells per one view look. Result: The Result of this experiment shows that expression of MHC-I and CD8+ in cervical cancer with HPV infection is in mild category (30% - 70%). Conclusion: Immunity against uterine cancer played by MHC-I and CD8+ is in milt category. The experiment that related with uterine cancer immunology is suggested.展开更多
Current cytotoxic T lymphocyte(CTL)activating immunotherapy requires a major histocompatibility complex I(MHC-I)-mediated presentation of tumor-associated antigens,which malfunctions in around half of patients with tr...Current cytotoxic T lymphocyte(CTL)activating immunotherapy requires a major histocompatibility complex I(MHC-I)-mediated presentation of tumor-associated antigens,which malfunctions in around half of patients with triple-negative breast cancer(TNBC).Here,we create a LCL161-loaded macrophage membrane decorated nanoparticle(LMN)for immunotherapy of MHC-I-deficient TNBC.SIRPa on the macrophage membrane helps LMNs recognize CD47-expressing cancer cells for targeted delivery of LCL161,which induces the release of high mobility group protein 1 and proinflammatory cytokines from cancer cells.The released cytokines and high mobility group protein 1 activate antitumor immunity by increasing the intratumoral density of the phagocytic macrophage subtype by 15 times and elevating the intratumoral concentration of CTL lymphotoxin by 4.6 folds.LMNs also block CD47-mediated phagocytosis suppression.LMNs inhibit the growth of MHC-I-deficient TNBC tumors,as well as those resistant to combined therapy of anti-PDL1 antibody and albumin-bound paclitaxel,and prolong the survival of animals,during which process CTLs also play important roles.This macrophage membrane-decorated nanoparticle presents a generalizable platform for increasing macrophagemediated antitumor immunity for effective immunotherapy of MHC-I-deficient cancers.展开更多
Adoptive immunotherapy involving the transfer of autologous tumor or virus-reactive T lymphocytes has been demonstrated to be effective in the eradication of cancer and virally infected cells. Identification of MHC-re...Adoptive immunotherapy involving the transfer of autologous tumor or virus-reactive T lymphocytes has been demonstrated to be effective in the eradication of cancer and virally infected cells. Identification of MHC-restricted antigens and progress in generation of adaptive immune responses have provided new direction for such treatment for severe pathologies such as cancer and autoimmune diseases. Here we review the latest development about the molecular basis of MHC-I/TCR interaction, and it＇s manipulation including enhanced MHC-I expression, modification of peptide and engineered TCR for clinical applications such as vaccine design, tumor therapy and autoimmune diseases.展开更多
目的探讨循环可溶性MHC-I类链相关蛋白A[soluble major histocompatibility complex class I-related chain A,sMICA)、可溶性MHC-I类链相关蛋白B(soluble major histocompatibility complex class I-related chain B,sMICB]与系统性红...目的探讨循环可溶性MHC-I类链相关蛋白A[soluble major histocompatibility complex class I-related chain A,sMICA)、可溶性MHC-I类链相关蛋白B(soluble major histocompatibility complex class I-related chain B,sMICB]与系统性红斑狼疮(systemic lupus erythematosus,SLE)疾病活动性、自身抗体的关系。方法选择2020年1月~2023年1月重庆大学附属黔江医院收治的156例SLE患者(SLE组)和门诊体检中心体检的103例健康志愿者(对照组)。根据SLE疾病活动度评分(SLE disease activity index,SLEDAI)将SLE患者分为轻度活动组(n=43)、中度活动组(n=69)和重度活动组(n=44)。检测血清sMICA,sMICB水平以及自身抗体、外周血NK细胞占比,Spearman或Pearson分析sMICA,sMICB与评分、自身抗体、外周血NK细胞占比的相关性,受试者工作特征(ROC)曲线用来分析sMICA和sMICB诊断SLE活动度的价值。结果SLE组血清sMICA(173.65±23.92 pg/ml),sMICB(96.35±15.74 pg/ml)水平高于对照组(32.51±6.27 pg/ml,12.03±2.47 pg/ml),外周血CD3^(-)CD56^(+)NK细胞(12.02%±2.65%)占比低于对照组(18.35%±3.71%),差异具有统计学意义(t=58.498,53.897,-16.010,均P<0.05)。重度活动组血清sMICA,sMICB水平高于中度活动组和轻度活动组(t=8.192,12.352;19.652,23.742,均P<0.05),外周血CD3^(-)CD56^(+)NK细胞占比低于中度活动组和轻度活动组(t=8.154,10.658,均P<0.05),差异具有统计学意义。不同疾病活动SLE患者抗‐dsDNA抗体、抗核抗体、抗核小体抗体和抗组蛋白抗体阳性率比较,差异具有统计学意义(χ^(2)=8.795,7.216,7.539,8.946,均P<0.05)。SLE患者血清sMICA,sMICB水平与SLEDAI评分、抗‐dsDNA抗体、抗核抗体、抗核小体抗体、抗组蛋白抗体呈正相关(r=0.206~0.402,均P<0.05),与外周血CD3^(-)CD56^(+)NK细胞占比呈负相关(r=-0.563,-0.427,均P<0.05)。sMICA和sMICB诊断SLE重度活动的曲线下面积为0.652,0.704,联合sMICA,sMICB诊断SLE重度活动的曲线下面积为0.812,高于单独诊断(Z=3.050,2.346,均P<0.05)。结论SLE患者血清sMICA和sMICB水平增高,且与SLE自身抗体阳性率增加、外周血NK细胞占比降低、疾病活动性增强有关,可作为SLE的潜在标志物。展开更多
Aim:Immunotherapy and immune checkpoint inhibitors(ICI)have changed cancer care for many patients;however,breast cancers have exhibited minimal response to single agent ICI therapy.There is a significant need to ident...Aim:Immunotherapy and immune checkpoint inhibitors(ICI)have changed cancer care for many patients;however,breast cancers have exhibited minimal response to single agent ICI therapy.There is a significant need to identify novel targets capable of increasing cancer cell immunogenicity and response to ICIs in breast cancer.Mitogen activated protein kinase(MAPK)signaling is essential for many cellular processes but the relationship between MAPK signaling and cancer cell immunogenicity is less well understood.Recent reports suggest that MEK inhibition(MEKi)affects the tumor-immune microenvironment by altering the expression of interferon responsive PD-L1 and MHC-I through unknown mechanisms.Methods:Using western blotting and flow cytometry,we sought to determine whether MEKi affects JAK-STAT signaling upstream of PD-L1 and MHC-I expression in a panel of mouse mammary cancer and triple negative breast cancer cell lines.Results:The cell lines tested exhibited increased STAT activation in response to MEKi treatment.Furthermore,MEKi-induced MHC-I and PD-L1 expression are dependent upon STAT1 in MMTV-Neu cells.Interestingly,MEKiinduced STAT activation and interferon-responsive protein expression are abrogated with ErbB-family inhibitor co-treatment in MMTV-Neu cells,suggesting ErbB receptor signaling dependence,but not in basal-like cell lines.Importantly,analysis of basal-like breast cancer patient samples exhibited an inverse relationship between STAT1 and Ras/MAPK activation signatures.Conclusion:These findings suggest that MAPK signaling and STAT activation are inversely related in both mouse and human mammary tumors.This work also supports further study of MEKi to increase STAT signaling and potentially,immunotherapy responses through increased MHC-I and PD-L1 expression.展开更多
文摘1 MHC-I Loss in the Immune Evasion of Cancer Cells Pancreatic ductal adenocarcinoma(PDAC)is a lethal cancer with a poor prognosis due to its aggressive nature and late detection.Recently,new discoveries in PDAC demonstrated receptor-interacting protein kinase 2(RIPK2)triggering immune evasion.Mechanistically,RIPK2 drives the desmoplastic tumor microenvironment(TME)and restricts the activation and density of tumor-infiltrating effector T cells by impairing the expression of major histocompatibility complex class I(MHC-I)[1].This process might be relevant in different solid cancer entities as illustrated by analyzing publicly available databases.
基金Supported by:the National Natural Science Foundation of China,No.30872530the Natural Science Foundation of Jiangsu Province,No.BK2007056the Key Talents Project of Health Department of Jiangsu Province,No.RC2007079~~
文摘Introduction: The immunity against cervical cancers is many unknown. Major histocompatability complex class I (MHC-I) with the alpha domain has binding site for Cytotoxic T cells (CD8+) to target cells. The objective of this experiment is to know the expression of CD8+ and MHC-I in cervical cancer with HPV infection. Method: DNA was isolated from seventeen sample cervical cancer tissues frozen section. Diagnose related with HPV was made by PCR. Paraffin block of the tissues was cut in thoroughly cleaned cryotome and place in glass plate that covered with poly-elysine. The immuno-histochemistry is done with monoclonal antibody again MHC-I and CD8+ with TSA-indirect method. The power of expression was counted the number of positive cells to express the MHC-I and CD8+ every 100 cells per one view look. Result: The Result of this experiment shows that expression of MHC-I and CD8+ in cervical cancer with HPV infection is in mild category (30% - 70%). Conclusion: Immunity against uterine cancer played by MHC-I and CD8+ is in milt category. The experiment that related with uterine cancer immunology is suggested.
基金financially supported by the National Natural Science Foundation of China(32371457,32171374 and 32130058)Shandong Laboratory Program(SYS202205,China).
文摘Current cytotoxic T lymphocyte(CTL)activating immunotherapy requires a major histocompatibility complex I(MHC-I)-mediated presentation of tumor-associated antigens,which malfunctions in around half of patients with triple-negative breast cancer(TNBC).Here,we create a LCL161-loaded macrophage membrane decorated nanoparticle(LMN)for immunotherapy of MHC-I-deficient TNBC.SIRPa on the macrophage membrane helps LMNs recognize CD47-expressing cancer cells for targeted delivery of LCL161,which induces the release of high mobility group protein 1 and proinflammatory cytokines from cancer cells.The released cytokines and high mobility group protein 1 activate antitumor immunity by increasing the intratumoral density of the phagocytic macrophage subtype by 15 times and elevating the intratumoral concentration of CTL lymphotoxin by 4.6 folds.LMNs also block CD47-mediated phagocytosis suppression.LMNs inhibit the growth of MHC-I-deficient TNBC tumors,as well as those resistant to combined therapy of anti-PDL1 antibody and albumin-bound paclitaxel,and prolong the survival of animals,during which process CTLs also play important roles.This macrophage membrane-decorated nanoparticle presents a generalizable platform for increasing macrophagemediated antitumor immunity for effective immunotherapy of MHC-I-deficient cancers.
文摘Adoptive immunotherapy involving the transfer of autologous tumor or virus-reactive T lymphocytes has been demonstrated to be effective in the eradication of cancer and virally infected cells. Identification of MHC-restricted antigens and progress in generation of adaptive immune responses have provided new direction for such treatment for severe pathologies such as cancer and autoimmune diseases. Here we review the latest development about the molecular basis of MHC-I/TCR interaction, and it＇s manipulation including enhanced MHC-I expression, modification of peptide and engineered TCR for clinical applications such as vaccine design, tumor therapy and autoimmune diseases.
基金Susan G.Komen Career Catalyst Grant CCR14299052(Balko JM),NIH/NCI SPORE 2P50CA098131-17(Balko JM),Department of Defense Era of Hope Award BC170037(Balko JM)the Vanderbilt-Ingram Cancer Center Support Grant P30 CA68485.Additional funding was provided by NIH T32GM007347(Axelrod ML)NIH T32CA009582-31(James JL)and F30CA236157(Axelrod ML).
文摘Aim:Immunotherapy and immune checkpoint inhibitors(ICI)have changed cancer care for many patients;however,breast cancers have exhibited minimal response to single agent ICI therapy.There is a significant need to identify novel targets capable of increasing cancer cell immunogenicity and response to ICIs in breast cancer.Mitogen activated protein kinase(MAPK)signaling is essential for many cellular processes but the relationship between MAPK signaling and cancer cell immunogenicity is less well understood.Recent reports suggest that MEK inhibition(MEKi)affects the tumor-immune microenvironment by altering the expression of interferon responsive PD-L1 and MHC-I through unknown mechanisms.Methods:Using western blotting and flow cytometry,we sought to determine whether MEKi affects JAK-STAT signaling upstream of PD-L1 and MHC-I expression in a panel of mouse mammary cancer and triple negative breast cancer cell lines.Results:The cell lines tested exhibited increased STAT activation in response to MEKi treatment.Furthermore,MEKi-induced MHC-I and PD-L1 expression are dependent upon STAT1 in MMTV-Neu cells.Interestingly,MEKiinduced STAT activation and interferon-responsive protein expression are abrogated with ErbB-family inhibitor co-treatment in MMTV-Neu cells,suggesting ErbB receptor signaling dependence,but not in basal-like cell lines.Importantly,analysis of basal-like breast cancer patient samples exhibited an inverse relationship between STAT1 and Ras/MAPK activation signatures.Conclusion:These findings suggest that MAPK signaling and STAT activation are inversely related in both mouse and human mammary tumors.This work also supports further study of MEKi to increase STAT signaling and potentially,immunotherapy responses through increased MHC-I and PD-L1 expression.
