Sufficiency of CD40 activation and immune checkpoint blockade for T cell priming and tumor immunity
- 25 March 2020
- journal article
- research article
- Published by Proceedings of the National Academy of Sciences in Proceedings of the National Academy of Sciences of the United States of America
- Vol. 117 (14), 8022-8031
- https://doi.org/10.1073/pnas.1918971117
Abstract
Innate immune receptors such as toll-like receptors (TLRs) provide critical molecular links between innate cells and adaptive immune responses. Here, we studied the CD40 pathway as an alternative bridge between dendritic cells (DCs) and adaptive immunity in cancer. Using an experimental design free of chemo- or radiotherapy, we found CD40 activation with agonistic antibodies (⍺CD40) produced complete tumor regressions in a therapy-resistant pancreas cancer model, but only when combined with immune checkpoint blockade (ICB). This effect, unachievable with ICB alone, was independent of TLR, STING, or IFNAR pathways. Mechanistically, αCD40/ICB primed durable T cell responses, and efficacy required DCs and host expression of CD40. Moreover, ICB drove optimal generation of polyfunctional T cells in this “cold” tumor model, instead of rescuing T cell exhaustion. Thus, immunostimulation via αCD40 is sufficient to synergize with ICB for priming. Clinically, combination αCD40/ICB may extend efficacy in patients with “cold” and checkpoint-refractory tumors.Funding Information
- HHS | NIH | National Cancer Institute (R01CA229803)
- HHS | NIH | National Cancer Institute (P01CA210944)
- Parker Institute for Cancer Immunotherapy (NA)
- HHS | NIH | National Cancer Institute (K12 CA076931)
- HHS | NIH | National Cancer Institute (K08 CA241084)
- HHS | National Institutes of Health (TL1TR001880)
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