biostudies-literatureWang XAmerican Association of ImmunologistsAmerican Cancer SocietyNIDCR NIH HHSU.S. Department of Health & Human Services | NIH | National Institute of Dental and Craniofacial ResearchU.S. Department of Health & Human Services | NIH | National Institute of Allergy and Infectious DiseasesNIAID NIH HHSU.S. Department of Health & Human Services | NIH | National Cancer InstituteCancer League of ColoradoNCI NIH HHS723-734https://www.ebi.ac.uk/biostudies/studies/S-EPMC8027191biostudies-literatureUnknown18(3)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.Cellular & molecular immunologyMHC class I-independent activation of virtual memory CD8 T cells induced by chemotherapeutic agent-treated cancer cells.PMC8027191R01-CA229174F31DE027854R21 CA184707ACS IRG #16-184-56R01 CA166325R21-AI110777T32 AI007405R01-CA166325Careers in Immunology FellowshipR21 AI133110R01 CA229174R21 AI110777R21-AI133110R21-CA184707F31 DE027854Chen SMYWaschke BCChen ZWang JHWang XWoolaver RAfalseMHC class I-independent activation of virtual memory CD8 T cells induced by chemotherapeutic agent-treated cancer cells.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.2021-01-01T00:00:00Z2021 Mar2025-04-27T01:42:50.024Z2025-04-06T18:21:25.416ZS-EPMC80271913242788310.1038/s41423-020-0463-2