[PDF][PDF] CD40 stimulation obviates innate sensors and drives T cell immunity in cancer

KT Byrne, RH Vonderheide - Cell reports, 2016 - cell.com
KT Byrne, RH Vonderheide
Cell reports, 2016cell.com
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 …
Summary
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.
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