title: Induced PD-L1 expression mediates acquired resistance to agonistic anti-CD40 treatment.
abstract: CD40 stimulation on antigen-presenting cells (APC) allows direct activation of CD8(+) cytotoxic T cells, independent of CD4⁺ T-cell help. Agonistic anti-CD40 antibodies have been demonstrated to induce beneficial antitumor T-cell responses in mouse models of cancer and early clinical trials. We report here that anti-CD40 treatment induces programmed death ligand-1 (PD-L1) upregulation on tumor-infiltrating monocytes and macrophages, which was strictly dependent on T cells and IFNγ. PD-L1 expression could be counteracted by coadministration of antibodies blocking the PD-1 (programmed death-1)/PD-L1 axis as shown for T cells from tumor models and human donors. The combined treatment was highly synergistic and induced complete tumor rejection in about 50% of mice bearing MC-38 colon and EMT-6 breast tumors. Mechanistically, this was reflected by a strong increase of IFNγ and granzyme-B production in intratumoral CD8⁺ T cells. Concomitant CTLA-4 blockade further improved rejection of established tumors in mice. This study uncovers a novel mechanism of acquired resistance upon agonistic CD40 stimulation and proposes that the concomitant blockade of the PD-1/PD-L1 axis is a viable therapeutic strategy to optimize clinical outcomes.
authors.affiliation: Cancer Immunology and Biology, Department of Biomedicine, University Hospital Basel and University of Basel, Switzerland. Department of Medical Oncology, University Hospital Basel, Switzerland. ph.mueller@unibas.ch alfred.zippelius@usb.ch.
authors.forename: Alfred
authors.initials: A
authors.lastname: Zippelius
authors.affiliation: Cancer Immunology and Biology, Department of Biomedicine, University Hospital Basel and University of Basel, Switzerland.
authors.forename: Jens
authors.initials: J
authors.lastname: Schreiner
authors.affiliation: Cancer Immunology and Biology, Department of Biomedicine, University Hospital Basel and University of Basel, Switzerland.
authors.forename: Petra
authors.initials: P
authors.lastname: Herzig
authors.affiliation: Cancer Immunology and Biology, Department of Biomedicine, University Hospital Basel and University of Basel, Switzerland. ph.mueller@unibas.ch alfred.zippelius@usb.ch.
authors.forename: Philipp
authors.initials: P
authors.lastname: Müller
mesh_terms: D000818:Animals; D000912:Antibodies, Neoplasm / Q000096:biosynthesis*; D000938:Antigen-Presenting Cells / Q000276:immunology; D060890:B7-H1 Antigen / Q000276:immunology*; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology*; D019013:CD40 Antigens / Q000819:agonists*; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology*; D060908:CTLA-4 Antigen / Q000037:antagonists & inhibitors; D045744:Cell Line, Tumor; D053804:Granzymes / Q000276:immunology; D006801:Humans; D016246:Lymphocytes, Tumor-Infiltrating / Q000187:drug effects*; D008264:Macrophages / Q000276:immunology; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D009000:Monocytes / Q000276:immunology
chemical_list: D000912:Antibodies, Neoplasm; D060890:B7-H1 Antigen; D019013:CD40 Antigens; D060908:CTLA-4 Antigen; D053804:Granzymes