CD40 Stimulation Obviates Innate Sensors and Drives T Cell Immunity in Cancer

Cancer immunotherapies are more effective in tumors with robust T cell infiltrates, but mechanisms to convert T cell-devoid tumors with active immunosuppression to those capable of recruiting T cells remain incompletely understood. Here, using genetically engineered mouse models of pancreatic ductal adenocarcinoma (PDA), we demonstrate that a single dose of agonistic CD40 antibody with chemotherapy rendered PDA susceptible to T cell-dependent destruction and potentiated durable remissions. CD40 stimulation caused a clonal expansion of T cells in the tumor, but the addition of chemotherapy optimized myeloid activation and T cell function. Although recent data highlight the requirement for innate sensors in cancer immunity, these canonical pathways—including TLRs, inflammasome, and type I interferon/STING—played no role in mediating the efficacy of CD40 and chemotherapy. Thus, CD40 functions as a non-redundant mechanism to convert the tumor microenvironment immunologically. Our data provide a rationale for a newly initiated clinical trial of CD40 and chemotherapy in PDA. [Display omitted] •CD40 stimulation converts T-cell-deficient tumors to immunologically replete sites•CD40 mediates clonal T cell expansion with decreased regulatory T cells•Functional adaptive immune responses require both CD40 stimulation and chemotherapy•Converted tumors undergo durable responses independently of innate immune sensors Immunologically “cold” tumors lack T cells and are hyporesponsive to immunotherapies. Byrne and Vonderheide show that CD40 stimulation, with chemotherapy, converts a “cold” tumor to a site of T cell infiltration and destruction with durable responses. Functional immune responses are independent of innate immune sensors important in other settings.