TY - JOUR
T1 - CD40 Stimulation Obviates Innate Sensors and Drives T Cell Immunity in Cancer
AU - Byrne, Katelyn T.
AU - Vonderheide, Robert H.
N1 - Publisher Copyright:
© 2016 The Author(s).
PY - 2016/6/21
Y1 - 2016/6/21
N2 - 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.
AB - 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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U2 - 10.1016/j.celrep.2016.05.058
DO - 10.1016/j.celrep.2016.05.058
M3 - Article
C2 - 27292635
AN - SCOPUS:84975105592
SN - 2211-1247
VL - 15
SP - 2719
EP - 2732
JO - Cell Reports
JF - Cell Reports
IS - 12
ER -