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

Cell Rep. 2016 Jun 21;15(12):2719-32. doi: 10.1016/j.celrep.2016.05.058. Epub 2016 Jun 9.

Abstract

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.

MeSH terms

  • Albumins / pharmacology
  • Albumins / therapeutic use
  • Animals
  • Antibodies / pharmacology
  • Antigen-Presenting Cells / metabolism
  • CD40 Antigens / metabolism*
  • CD8-Positive T-Lymphocytes / drug effects
  • CD8-Positive T-Lymphocytes / immunology
  • Carcinoma, Pancreatic Ductal / drug therapy
  • Carcinoma, Pancreatic Ductal / immunology
  • Carcinoma, Pancreatic Ductal / pathology
  • Clone Cells
  • Deoxycytidine / analogs & derivatives
  • Deoxycytidine / pharmacology
  • Deoxycytidine / therapeutic use
  • Immunity, Innate* / drug effects
  • Interferon-gamma / metabolism
  • Lymphocyte Subsets / drug effects
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Neoplasms / immunology*
  • Neoplasms / pathology
  • Paclitaxel / pharmacology
  • Paclitaxel / therapeutic use
  • Pancreatic Neoplasms / drug therapy
  • Pancreatic Neoplasms / immunology
  • Pancreatic Neoplasms / pathology
  • T-Lymphocytes / drug effects
  • T-Lymphocytes / immunology*
  • Treatment Outcome
  • Tumor Microenvironment / drug effects

Substances

  • 130-nm albumin-bound paclitaxel
  • Albumins
  • Antibodies
  • CD40 Antigens
  • Deoxycytidine
  • Interferon-gamma
  • gemcitabine
  • Paclitaxel

Supplementary concepts

  • Pancreatic Carcinoma