Prospective and genetic analyses implicate lower immunosurveillance in the aetiology of prostate cancer

Tumour promoting inflammation and the ability to evade immune destruction are two of the hallmarks of cancer, but there is limited prospective evidence for the role of specific inflammation and immune-related pathways and protein markers in the development of prostate cancer. This study used data on the circulating levels of 368 inflammation and immune-related proteins (Olink Explore Inflammation I panel) from a nested case-control design within the European Prospective Investigation into Cancer and Nutrition (EPIC), including 1,434 men who developed prostate cancer and 1,434 matched controls − 488 of the cases also had clinically aggressive disease. Conditional logistic regression was used to estimate protein associations with cancer risk in EPIC, per standard deviation and the effective number of tests (ENT) was used to control for multiple testing. We additionally performed an inverse-variance weighted meta-analysis combining associations for these proteins estimated in EPIC with those in 21,481 men from UK Biobank (UKBB), of whom 1,147 developed prostate cancer. Logistic regression was used to estimate exome protein score association with cancer risk in UKBB and replication analyses were performed in the Multiethnic Cohort (MEC). Mendelian randomisation and colocalisation analyses using data on 79,148 overall prostate cancer cases from the PRACTICAL consortium were also conducted to aid triangulation. In EPIC, no inflammatory proteins were associated with prostate cancer risk overall or with more clinically aggressive subtypes after correction for multiple testing. In the EPIC + UKBB meta-analyses, FLT3LG and CNTNAP2 were significantly associated with overall prostate cancer risk (RR _Meta :0.88, 95%CI:0.84–0.92 and RR _Meta :1.10, 95%CI:1.05–1.16, respectively), and in the analyses stratified by time to diagnosis, IL15 was associated with risk of prostate cancer diagnosed more than seven years after blood draw (RR _Meta :0.86, 95%CI:0.81–0.93), along with five other proteins (FLT3LG, BCL2L11, PGF, CKAP4, and TNFRSF11A). Exome protein scores in UKBB provided some support for IL15 and FLT3LG and also identified PARP1 as associated with an increased risk of prostate cancer (OR:1.05, 95%CI:1.02–1.07), which replicated in MEC (OR:1.04, 95%CI:1.01–1.08). MR and colocalisation analyses also identified SPINT2 (OR:2.11, 95%CI:1.70–2.63) and NME3 (OR:1.25, 95%CI:1.11–1.41) as being associated with an increased risk of prostate cancer overall. Our findings suggest higher levels of proteins involved in immunosurveillance pathways, including the recruitment and activation of natural killer and T cells, may be linked to a lower risk of developing prostate cancer, while PARP1 inhibition may be relevant for prostate cancer prevention.