In two mouse tumor models, the PD-1+ subset of CD8+ TILs contained the majority of tumor-specific cells, which could thus be readily isolated without previous knowledge of their antigen specificities. The PD-1+ CD8+ T cells (expanded in vitro) were better than their PD-1- or bulk CD8+ counterparts at containing tumor progression in vivo, and their efficacy was enhanced by PD-L1 blockade.
Recent studies have found that tumor-infiltrating lymphocytes (TIL) expressing PD-1 can recognize autologous tumor cells, suggesting that cells derived from PD-1+ TIL can be used in adoptive T cell therapy (ACT). However, no study thus far has evaluated the antitumor activity of PD-1-selected TIL in vivo. In two mouse models of solid tumors, we show that PD-1 allows identification and isolation of tumor-specific TIL without previous knowledge of their antigen specificities. Importantly, despite the high proportion of tumor-reactive T cells present in bulk CD8 TIL before expansion, only T cell products derived from sorted PD-1+, but not from PD-1- or bulk CD8 TIL, specifically recognized tumor cells. The fold-expansion of PD-1+ CD8 TIL was 10 times lower than that of PD-1- cells, suggesting that outgrowth of PD-1- cells was the limiting factor in the tumor specificity of cells derived from bulk CD8 TIL. The highly differentiated state of PD-1+ cells was likely the main cause hampering ex vivo expansion of this subset. Moreover, PD-1 precisely identified marrow-infiltrating, myeloma-specific T cells in a mouse model of multiple myeloma. In vivo, only cells expanded from PD-1+ CD8 TIL contained tumor progression, and their efficacy was enhanced by PDL-1 blockade. Overall, our data provide a rationale for the use of PD-1-selected TIL in ACT.
Author Info: (1) Immunology and Immunotherapy Program, Center for Applied Medical Research (CIMA), University of Navarra. (2) Oncology Department, University Clinic, University of Navarra. (3)
Author Info: (1) Immunology and Immunotherapy Program, Center for Applied Medical Research (CIMA), University of Navarra. (2) Oncology Department, University Clinic, University of Navarra. (3) Immunology and Immunotherapy Program, Center for Applied Medical Research (CIMA), University of Navarra. (4) Division of Hepatology and Gene Therapy, University of Navarra, Center for Applied Medical Research (CIMA). (5) Centre for Nutrition Research, University of Navarra. (6) Oncology, CIMA. (7) Immunology and Immunotherapy Program, Center for Applied Medical Research (CIMA), University of Navarra. (8) Hematology, Clinica Universidad de Navarra, Centro de Investigacion Medica Aplicada (CIMA), IDISNA. (9) Immunology and Immunotherapy Program, Center for Applied Medical Research (CIMA), University of Navarra. (10) Immunology and Immunotherapy Program, Center for Applied Medical Research (CIMA), University of Navarra. (11) Immunology and Immunotherapy Program, Center for Applied Medical Research (CIMA), University of Navarra. (12) Program of Immunology and Immunotherapy, University of Navarra, Center for Applied Medical Research (CIMA). (13) Immunology and Immunotherapy Program, Center for Applied Medical Research (CIMA), University of Navarra. (14) Immunology and Immunotherapy Program, Center for Applied Medical Research (CIMA), University of Navarra mshervas@unav.es.
