Morrison et al. investigated the link between the CD40 pathway and adaptive immunity. In the KPC model of pancreatic ductal adenocarcinoma, combination of agonist αCD40 with dual ICB (αCTLA-4/αPD-1) caused s.c. and orthotopic tumor regression with immunological memory, without radiotherapy or chemotherapy, while dual ICB or αCD40 alone were ineffective. Mechanistically, efficacy required DCs, CD4+ and CD8+ T cells, and CD40 host expression, and was independent of TLR, STING, and type I IFN pathways. CD40 activation with ICB was sufficient in priming a robust polyfunctional T cell response without evidence of reversing T cell exhaustion in the tumor.
Contributed by Katherine Turner
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, alphaCD40/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 alphaCD40 is sufficient to synergize with ICB for priming. Clinically, combination alphaCD40/ICB may extend efficacy in patients with "cold" and checkpoint-refractory tumors.
Author Info: (1) Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104. (2) Department of Medicine, Perelman School of Medicine, University of
Author Info: (1) Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104. (2) Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104. (3) Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104. (4) Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104; byrnek@upenn.edu rhv@upenn.edu. Parker Institute for Cancer Immunotherapy, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104. (5) Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104; byrnek@upenn.edu rhv@upenn.edu. Parker Institute for Cancer Immunotherapy, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104. Abramson Cancer Center, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104.
