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
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
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
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
It has been reported that the ratio of CD41 to CD81 T cells has no bias in a few class I major histocompatibility complex(MHC-I)-restricted T-cell receptor(TCR)-transgenic mice specific for alloantigens or autoantigen...It has been reported that the ratio of CD41 to CD81 T cells has no bias in a few class I major histocompatibility complex(MHC-I)-restricted T-cell receptor(TCR)-transgenic mice specific for alloantigens or autoantigens,in which most CD41 T cells express an MHC-I-restricted TCR.In this study,we further showed that more than 50%of CD41 T cells in MHC-I-restricted P1A tumor antigen-specific TCR(P1ATCR)-transgenic mice could specifically bind to MHC-I/P1A peptide complex.P1A peptide could stimulate the transgenic CD41 T cells to proliferate and secrete both type 1 helper T cell and type 2 helper T cell cytokines.The activated CD41 T cells also showed cytotoxicity against P1A-expressing tumor cells.The analysis of TCR a-chains showed that these CD41 T cells were selected by co-expressing endogenous TCRs.Our results show that CD41 T cells from P1ATCR transgenic mice co-expressed an MHC-I-restricted transgenic TCR and another rearranged endogenous TCRs,both of which were functional.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.
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.
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.
基金grants from the National Natural Science Foundation of China under contract no.30771968.
文摘It has been reported that the ratio of CD41 to CD81 T cells has no bias in a few class I major histocompatibility complex(MHC-I)-restricted T-cell receptor(TCR)-transgenic mice specific for alloantigens or autoantigens,in which most CD41 T cells express an MHC-I-restricted TCR.In this study,we further showed that more than 50%of CD41 T cells in MHC-I-restricted P1A tumor antigen-specific TCR(P1ATCR)-transgenic mice could specifically bind to MHC-I/P1A peptide complex.P1A peptide could stimulate the transgenic CD41 T cells to proliferate and secrete both type 1 helper T cell and type 2 helper T cell cytokines.The activated CD41 T cells also showed cytotoxicity against P1A-expressing tumor cells.The analysis of TCR a-chains showed that these CD41 T cells were selected by co-expressing endogenous TCRs.Our results show that CD41 T cells from P1ATCR transgenic mice co-expressed an MHC-I-restricted transgenic TCR and another rearranged endogenous TCRs,both of which were functional.
