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.
Author Info: (1) Department of Pathology and Immunology, Washington University in St. Louis, School of Medicine, St. Louis, MO, USA. (2) Department of Pathology and Immunology, Washington Unive
Author Info: (1) Department of Pathology and Immunology, Washington University in St. Louis, School of Medicine, St. Louis, MO, USA. (2) Department of Pathology and Immunology, Washington University in St. Louis, School of Medicine, St. Louis, MO, USA. (3) Department of Pathology and Immunology, Washington University in St. Louis, School of Medicine, St. Louis, MO, USA. (4) Department of Pathology and Immunology, Washington University in St. Louis, School of Medicine, St. Louis, MO, USA. (5) Department of Pathology and Immunology, Washington University in St. Louis, School of Medicine, St. Louis, MO, USA. (6) Department of Pathology and Immunology, Washington University in St. Louis, School of Medicine, St. Louis, MO, USA. (7) Department of Pathology and Immunology, Washington University in St. Louis, School of Medicine, St. Louis, MO, USA. (8) Department of Pathology and Immunology, Washington University in St. Louis, School of Medicine, St. Louis, MO, USA. (9) Department of Pathology and Immunology, Washington University in St. Louis, School of Medicine, St. Louis, MO, USA. (10) Department of Surgery, Washington University in St. Louis, School of Medicine, St. Louis, MO, USA. (11) Department of Neurology, University of North Carolina School of Medicine, Chapel Hill, NC, USA. Department of Pediatrics, ECC Room 254, Emory University School of Medicine, Atlanta, GA, USA. (12) Department of Pathology and Immunology, Washington University in St. Louis, School of Medicine, St. Louis, MO, USA. The Andrew M. and Jane M. Bursky Center for Human Immunology and Immunotherapy Programs, Washington University School of Medicine, St Louis, MO, USA. Parker Institute for Cancer Immunotherapy, San Francisco, CA, USA. (13) Department of Pathology and Immunology, Washington University in St. Louis, School of Medicine, St. Louis, MO, USA. (14) Department of Pathology and Immunology, Washington University in St. Louis, School of Medicine, St. Louis, MO, USA. kmurphy@wustl.edu.
