Wu et al. showed that the most highly induced genes following CD40 activation of murine migratory cDC1s were CD70, 4-1BBL, COX-2, Bcl-xL and Bcl-xS. In tumor models requiring CD40+ cDC1s for rejection, cDC1-specific CD70 or COX-2 deletion at most partially reduced rejection and tumor-specific CD8+ T cell expansion, whereas cDC1 loss of Bcl-xL markedly reduced specific CD8+ T cell expansion. cDC1-specific CD40 deletion reduced cDC1s’ mitochondrial transmembrane potential, increased caspase activation in tumor-draining LNs, and reduced migratory cDC1 numbers. Bcl-xL promoted cDC1 survival during priming to boost CD8+ T cell expansion and antitumor response.
Contributed by Paula Hochman
ABSTRACT: CD40 signaling in classical type 1 dendritic cells (cDC1s) is required for CD8 T cell-mediated tumor rejection, but the underlying mechanisms are incompletely understood. Here, we identified CD40-induced genes in cDC1s, including Cd70, Tnfsf9, Ptgs2 and Bcl2l1, and examined their contributions to anti-tumor immunity. cDC1-specific inactivation of CD70 and COX-2, and global CD27 inactivation, only partially impaired tumor rejection or tumor-specific CD8 T cell expansion. Loss of 4-1BB, alone or in Cd27(-/-) mice, did not further impair anti-tumor immunity. However, cDC1-specific CD40 inactivation reduced cDC1 mitochondrial transmembrane potential and increased caspase activation in tumor-draining lymph nodes, reducing migratory cDC1 numbers in vivo. Similar impairments occurred during in vitro antigen presentation by Cd40(-/-) cDC1s to CD8(+) T cells, which were reversed by re-expression of Bcl2l1. Thus, CD40 signaling in cDC1s not only induces costimulatory ligands for CD8(+) T cells but also induces Bcl2l1 that sustains cDC1 survival during priming of anti-tumor responses.