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Investigating the repurposing potential of immune checkpoint inhibition for cancer treatment using Mendelian
Tessa Bate1, Mei Dong2, Yuxi Liu3
1University of Bristol.
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.
Insights
Investigating immune checkpoint proteins programmed cell death protein 1 (PD-1) and PD-L1, this study suggests PD-1 inhibitor repurposing for ovarian, colorectal, and early-stage lung cancers. PD-L1 inhibitor effectiveness was not recapitulated in this analysis.
Area of Science:
- Oncology
- Immunology
- Genetics
Background:
- Programmed cell death protein 1 (PD-1) and programmed death ligand-1 (PD-L1) are key immune checkpoint proteins exploited by tumors to evade immune responses.
- Current PD-1/PD-L1 inhibitor therapies are approved for specific cancer types and patient populations, limiting broader clinical application.
Purpose of the Study:
- To explore the potential for repurposing PD-1 and PD-L1 inhibitors in additional cancer patient groups.
- To investigate the association between germline genetic variation proxying for lower plasma PD-1 or PD-L1 levels and mortality risk in various cancer types.
Main Methods:
- A Mendelian randomization approach was employed using germline genetic variants as instrumental variables.
- The study analyzed mortality risk (all-cause and cancer-specific) in patients diagnosed with breast, colorectal, lung, melanoma, ovarian, and prostate cancers.
Main Results:
- For cancers with current PD-1/L1 inhibitor approvals, a decrease in germline proxied plasma PD-1 levels was associated with reduced mortality (HR: 0.91 [0.84-0.98]).
- The PD-L1 instrument did not replicate expected pharmaceutical effects (HR: 0.98 [0.92-1.05]), suggesting limitations in germline proxies for tumor PD-L1.
- Evidence supports PD-1 inhibitor repurposing for ovarian cancer (HR: 0.88 [0.78-0.99]), broader colorectal cancer (HR: 0.84 [0.71-1.00]), and early-stage lung cancer (HR: 0.75 [0.61-0.93]).
Conclusions:
- Germline PD-1 lowering shows potential for repurposing PD-1 inhibitors in ovarian, colorectal, and early-stage lung cancers.
- The study highlights methodological challenges in using germline proxies for PD-1/PD-L1 pathway analysis and suggests caution in interpretation.
