Investigating the repurposing potential of immune checkpoint inhibition for cancer treatment using Mendelian randomisation
Year: 2026
Type: preprint
Study design: Observational Study
Abstract: 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.
Source: Research Square
Authors: Tessa Bate, Mei Dong, Yuxi Liu, Mathias Seviiri, M. Catherine Brown, Joshua Atkins, Karl Smith-Byrne, Rayjean Hung, Matthew Law, Mark Iles, Hadis Ghajari, Serigne Lo, Alexander Gusev, Brett Vanderwerff, Sebastian Zoellner, Geoffrey Liu, Wei Xu, Richard Martin, James Yarmolinsky, Philip Haycock
Institutions: University of Bristol, University of Toronto, Brigham and Women's Hospital, QIMR Berghofer Medical Research Institute, University Health Network, Princess Margaret Cancer Centre, University of Oxford, Institute of Cancer Research, University of Leeds, The University of Sydney, Melanoma Institute Australia, Dana-Farber Cancer Institute, Imperial College London
Language: English
Subfield: Oncology
Field: Medicine
Domain: Health Sciences
Open Access status: green
Funders: Breast Cancer Research Foundation, Ovarian Cancer Research Fund, National Cancer Research Institute, Pancreatic Cancer UK, Royal Marsden NHS Foundation Trust, University Hospitals Bristol NHS Foundation Trust, NIHR Bristol Biomedical Research Centre, Cancer Research UK, National Institute for Health and Care Research, Department of Health and Social Care, European Commission, Rosetrees Trust, University of Bristol, National Institutes of Health, Manchester Biomedical Research Centre, Canadian Institutes of Health Research, Medical Research Council, Cancer Council Victoria, Cancer Council Queensland, National Cancer Institute
Awards: G1079453547, G108412983, G1136991791, G1161123863, G1164366582, A genome-wide association study for breast cancer in BRCA1 mutation carriers, G1227813248, Imputation-based approach to identify low frequency variants in prostate cancer, G1435186909, G1508859565, G1584405745, G1588059303, G1589121050, G1616122786, G1767914659, G1938717030, G2073849179, G2084344077, G2233787151, G2313227773, G236237718, G2445392763, G2453522775, G2514702731, Discovery, Biology and Risk of Inherited Variants in Breast Cancer, G2644099113, G2854377419, G2953759644, G2993358891, PCPT and SELECT cohorts: Core Infrastructure Support for Cancer Research, G3177576377, G3188551179, G3248832364, G3295228044, G3545110800, G3607452959, Elucidating Loci Involved in Prostate Cancer Suceptibility, G3794179797, G380538514, G3891343362, G3933833023, G3981421899, G4043398722, G4044476773, G4098640521, G4167275758, G4197410787, G4210055352, G421870969, G4333708648, G4393399965, G4639802573, G4662672464, G4806032448, G497649239, G5019474394, G5035440390, G5048543170, G5373760811, G5395379871, G5486405922, G5536876699, G5681652998, G5800550979, G586064783, G60573655, G6228767644, G6294906247, G6301433572, G6366270716, Follow-up of Ovarian Cancer Genetic Association and Interaction Studies (FOCI), G6662549690, G6794500166, G6858204494, G7006486244, G7206692317, G7372524322, G7383316951, G7410254275, G7557895011, G7570682278, SWOG Community Clinical Oncology Program Research Base, G790382466, G8062165187, G8092145710, G8209208257, G8344269847, Collaborative Oncological Gene-environment Study, G856283587, G8834430567, G8853615787, G8854317076, G8908128081, G8924490982, G8959936493, G8974852769, G9000048109, G9000200580, G9000282203, G9000301350, G961278264
OpenAlex ID: W7171528059