Cancer cells can evade immune recognition by losing major histocompatibility complex(MHC)class Ⅰ.Hence,MHC class Ⅰ-negative cancers represent the most challenging cancers to treat.Chemotherapeutic drugs not only dir...Cancer cells can evade immune recognition by losing major histocompatibility complex(MHC)class Ⅰ.Hence,MHC class Ⅰ-negative cancers represent the most challenging cancers to treat.Chemotherapeutic drugs not only directly kill tumors but also modulate the tumor immune microenvironment However,it remains unknown whether chemotherapy-treated cancer cells can activate CD8 T cells independent of tumor-derived MHC class Ⅰ and whether such MHC class Ⅰ-independent CD8 T-cell activation can be exploited for cancer immunotherapy.Here,we showed that chemotherapy-treated cancer cells directly activated CD8 T cells in an MHC class Ⅰ-independent manner and that these activated CD8 T cells exhibit virtual memory(VM)phenotypes.Consistently,in vivo chemotherapeutic treatment preferentially increased tumor-infiltrating VM CD8 T cells.Mechanistically,MHC class Ⅰ-independent activation of CD8 T cells requires cell-cell contact and activation of the PI3K pathway.VM CD8 T cells contribute to a superior therapeutic effect on MHC class Ⅰ-deficient tumors.Using humanized mouse models or primary human CD8 T cells,we also demonstrated that chemotherapy-treated human lymphomas activated VM CD8 T cells independent of tumor-derived MHC class Ⅰ.In conclusion,CD8 T cells can be directly activated in an MHC class Ⅰ-independent manner by chemotherapy-treated cancers,and these activated CD8 T cells may be exploited for developing new strategies to treat MHC class Ⅰ-deficient cancers.展开更多
基金supported by University of Colorado School of Medicine and Cancer Center startup funds to JHW,Cancer League of Colorado grants R21-CA184707,R21-Al110777,R01-CA166325,R21 Al133110,and R01-CA229174 to J.H.W.a fund from American Cancer Society(ACS IRG#16-184-56)to Z.C.X.W.was supported by an AAI Careers in Immunology Fellowship+1 种基金supported by an NIH F31 fellowship(F31DE027854)supported by an NIH T32 fellowship(T32 AI007405).
文摘Cancer cells can evade immune recognition by losing major histocompatibility complex(MHC)class Ⅰ.Hence,MHC class Ⅰ-negative cancers represent the most challenging cancers to treat.Chemotherapeutic drugs not only directly kill tumors but also modulate the tumor immune microenvironment However,it remains unknown whether chemotherapy-treated cancer cells can activate CD8 T cells independent of tumor-derived MHC class Ⅰ and whether such MHC class Ⅰ-independent CD8 T-cell activation can be exploited for cancer immunotherapy.Here,we showed that chemotherapy-treated cancer cells directly activated CD8 T cells in an MHC class Ⅰ-independent manner and that these activated CD8 T cells exhibit virtual memory(VM)phenotypes.Consistently,in vivo chemotherapeutic treatment preferentially increased tumor-infiltrating VM CD8 T cells.Mechanistically,MHC class Ⅰ-independent activation of CD8 T cells requires cell-cell contact and activation of the PI3K pathway.VM CD8 T cells contribute to a superior therapeutic effect on MHC class Ⅰ-deficient tumors.Using humanized mouse models or primary human CD8 T cells,we also demonstrated that chemotherapy-treated human lymphomas activated VM CD8 T cells independent of tumor-derived MHC class Ⅰ.In conclusion,CD8 T cells can be directly activated in an MHC class Ⅰ-independent manner by chemotherapy-treated cancers,and these activated CD8 T cells may be exploited for developing new strategies to treat MHC class Ⅰ-deficient cancers.
