Induced PD-L1 expression mediates acquired resistance to agonistic anti-CD40 treatment

Abstract

CD40 stimulation on antigen presenting cells (APCs) allows direct activation of CD8+ cytotoxic T-cells, independent of CD4+ T-cell help. Agonistic anti-CD40 antibodies have been demonstrated to induce beneficial anti-tumor 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 interferon-γ (IFN-γ). PD-L1 expression could be counteracted by co-administration 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 IFN-γ and granzyme-B production in intra-tumoral 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.