Investigating the repurposing potential of immune checkpoint inhibition for cancer treatment using Mendelian randomisation

Programmed cell death protein 1 (PD-1) and programmed death ligand-1 (PD-L1) are immune checkpoint proteins involved in tumour evasion of immune suppression. Inhibitors of these proteins are approved to treat cancer patients restricted by criteria such as site and immunologically ‘hot’ tumour features. To assess their repurposing potential to additional cancer patient populations, we used a Mendelian randomisation approach to investigate the effects of germline proxied plasma PD-1 or PD-L1 lowering on all-cause or cancer-specific mortality risk after diagnosis of cancers with (breast, colorectal, lung, melanoma) or without (ovarian, prostate) PD-1 and PD-L1 inhibitor approvals. Across the four studied cancers with current PD-1/L1 inhibitor approvals, hazard ratios (HRs) for mortality [95% confidence intervals] per standard deviation decrease in germline proxied plasma protein levels were PD-1:0.91 [0.84–0.98]; PD-L1:0.98 [0.92–1.05]. This suggests failure of the PD-L1 instrument to recapitulate known pharmaceutical effects of PD-L1 inhibition, potentially due to germline proxies not robustly reflecting tumour PD-L1 mechanisms. There was evidence to support PD-1 inhibitor repurposing for a novel indication, ovarian cancer treatment (HR = 0.88 [0.78–0.99]), and to broader colorectal (HR = 0.84 [0.71-1.00]) and early-stage lung (HR = 0.75 [0.61–0.93]) cancer populations than current approvals. Where possible, methodological considerations were addressed but findings should be interpreted with caution.