Sufficiency of CD40 activation and immune checkpoint blockade for T cell priming and tumor immunity

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...

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Bibliographic Details
Published in:Proceedings of the National Academy of Sciences - PNAS 2020-04, Vol.117 (14), p.8022-8031
Main Authors: Morrison, Alexander H., Diamond, Mark S., Hay, Ceire A., Byrne, Katelyn T., Vonderheide, Robert H.
Format: Article
Language:English
Subjects:
Activation
Adaptive immunity
Antibodies
Biological Sciences
Cancer
CD40 antigen
Dendritic cells
Design of experiments
Exhaustion
Experimental design
Immune checkpoint
Immune system
Immunity
Immunostimulation
Lymphocytes
Lymphocytes T
Pancreas
Pancreatic cancer
Priming
Proteins
Radiation therapy
Receptors
Synergism
Toll-like receptors
Tumors
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Summary: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.
ISSN:0027-8424
1091-6490
DOI:10.1073/pnas.1918971117