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.
Abramson Cancer Center and Department of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
Katelyn T
KT
Byrne
Abramson Cancer Center and Department of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA. Electronic address: rhv@exchange.upenn.edu.
Robert H
RH
Vonderheide
D000418:Albumins / Q000494:pharmacology / Q000627:therapeutic use; D000818:Animals; D000906:Antibodies / Q000494:pharmacology; D000938:Antigen-Presenting Cells / Q000378:metabolism; D019013:CD40 Antigens / Q000378:metabolism*; D018414:CD8-Positive T-Lymphocytes / Q000187:drug effects / Q000276:immunology; D021441:Carcinoma, Pancreatic Ductal / Q000188:drug therapy / Q000276:immunology / Q000473:pathology; D002999:Clone Cells; D003841:Deoxycytidine / Q000031:analogs & derivatives / Q000494:pharmacology / Q000627:therapeutic use; D007113:Immunity, Innate / Q000187:drug effects; D007371:Interferon-gamma / Q000378:metabolism; D016131:Lymphocyte Subsets / Q000187:drug effects; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009369:Neoplasms / Q000276:immunology* / Q000473:pathology; D017239:Paclitaxel / Q000494:pharmacology / Q000627:therapeutic use; D010190:Pancreatic Neoplasms / Q000188:drug therapy / Q000276:immunology / Q000473:pathology; D013601:T-Lymphocytes / Q000187:drug effects / Q000276:immunology*; D016896:Treatment Outcome; D059016:Tumor Microenvironment / Q000187:drug effects; D000093542:Gemcitabine
C520255:130-nm albumin-bound paclitaxel; D000418:Albumins; D000906:Antibodies; D019013:CD40 Antigens; D003841:Deoxycytidine; D007371:Interferon-gamma; D017239:Paclitaxel; D000093542:Gemcitabine