Pharmacologic tumor PDL1 depletion as a novel approach to overcome treatment resistance

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Abstract Tumor surface PDL1 canonically engages immune cell PD1 to inhibit anti-tumor immunity. However, PDL1 also mediates tumor-intrinsic pathologic signals, including promoting the DNA damage response (DDR) and suppressing immunogenic STING. Genetic tumor PDL1 depletion (CRISPR/Cas9, shRNA) induces novel treatment vulnerabilities that are not replicated by αPDL1 antibodies, but genetic tumor PDL1 depletion is not clinically feasible. We hypothesized that pharmacologic tumor PDL1 depletion could replicate genetic PDL1 depletion effects as a highly translational strategy to create novel treatment vulnerabilities. We conducted a high-throughput drug screen that identified 15 tumor PDL1 depleting drugs (PDDs) that potently reduce tumor PDL1 and are FDA-approved. Cefepime (β-lactam antibiotic) is a PDD that induced PDL1-dependent Chk2 DDR protein depletion (immunoblots), Chk1 inhibitor sensitivity in vitro (MTT, p<0.0001) and in vivo in wild-type and NSG mice (p=0.03), and immunogenic STING signals (immunoblots, RT-qPCR). The PDD telmisartan (angiotensin II receptor blocker) induced PARP inhibitor sensitivity in vitro (p<0.0001), impaired homologous recombination DDR (DR-GFP reporter, immunoblots), and induced STING signals and immunogenic cell death (flow cytometry). The PDD chlorambucil (alkylating agent) selectively depleted tumor PDL1 in vivo and sensitized αPDL1-resistant tumors to αPDL1 in a tumor PDL1 and NK cell-dependent manner. Thus, PDDs deplete tumor PDL1 to inhibit its pathologic cell-intrinsic signals, induce novel treatment vulnerabilities, improve tumor immunogenicity, and are rapidly translatable. Supported by grants from NIH (Graduate Research in Immunology Program training grant T32 AI138944, TL1 TR002647, T32GM113896, CA204965, CA054515) and the Clayton Foundation (no grant number).

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