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

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

Author information

1
Abramson Cancer Center and Department of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
2
Abramson Cancer Center and Department of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA. Electronic address: rhv@exchange.upenn.edu.

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.

PMID:
27292635
PMCID:
PMC4917417
DOI:
10.1016/j.celrep.2016.05.058
[Indexed for MEDLINE]
Free PMC Article

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