Polygenic risk score for ulcerative colitis predicts immune checkpoint inhibitor-mediated colitis

Abstract

Immune checkpoint inhibitors (ICIs) are a remarkable advancement in cancer therapeutics; however, a substantial proportion of patients develop severe immune-related adverse events (irAEs). Understanding and predicting irAEs is a key to advancing precision immuno-oncology. Immune checkpoint inhibitor-mediated colitis (IMC) is a significant complication from ICI and can have life-threatening consequences. Based on clinical presentation, IMC mimics inflammatory bowel disease, however the link is poorly understood. We hypothesized that genetic susceptibility to Crohn's disease (CD) and ulcerative colitis (UC) may predispose to IMC. We developed and validated polygenic risk scores for CD (PRS_CD) and UC (PRS_UC) in cancer-free individuals and assessed the role of each of these PRSs on IMC in a cohort of 1,316 patients with non-small cell lung cancer who received ICIs. Prevalence of all-grade IMC in our cohort was 4% (55 cases), and for severe IMC, 2.5% (32 cases). The PRS_UC predicted the development of all-grade IMC (HR=1.34 per standard deviation [SD], 95% CI=1.02-1.76, P=0.04) and severe IMC (HR=1.62 per SD, 95% CI=1.12-2.35, P=0.01). PRS_CD was not associated with IMC or severe IMC. The association between PRS_UC and IMC (all-grade and severe) was consistent in an independent pan-cancer cohort of patients treated with ICIs. Furthermore, PRS_UC predicted severe IMC among patients treated with combination ICIs (OR = 2.20 per SD, 95% CI = 1.07-4.53, P=0.03). This is the first study to demonstrate the potential clinical utility of a PRS for ulcerative colitis in identifying patients receiving ICI at high risk of developing IMC, where risk reduction and close monitoring strategies could help improve overall patient outcomes.

Figure 1:. Overview of the analytical pipeline.

Development and validation of the polygenic risk scores (PRSs): LDPred2 method was used to tune the parameters for the PRS for ulcerative colitis and Crohn’s disease (PRS_UC, PRS_CD) in 70% of the UK Biobank, using the summary statistics from the largest genome-wide association study of UC and CD. The PRSs were then tested in the remaining 30% of the UK Biobank and validated in BioVU. In the next step, the role of PRS_UC and PRS_CD on all-grade and severe immune checkpoint inhibitor-mediated colitis (IMC) was evaluated in a cohort of 1,316 non-small cell lung cancer patients who received at least one dose of immune checkpoint inhibitor therapy. Furthermore, replication was conducted using 873 pancancer patients treated with immune checkpoint inhibitors obtained from BioVU. Finally, associations of all-grade and severe IMC along with PRS_UC and PRS_CD on progression-free survival (PFS) and overall survival (OS) were assessed.

Figure 2:

Cumulative incidence curves of (i) All-grade immune checkpoint inhibitor-mediated colitis (IMC) and (ii) Severe IMC by categories of polygenic risk score of ulcerative colitis (PRS_UC) in the entire GeRI cohort. PRS_UC is categorized as ≤10th percentile (low genetic risk), 10–90th percentile (average genetic risk), and >90th percentile (high genetic risk).

Figure 3:

Immune checkpoint inhibitor-mediated colitis (IMC) as a predictor of overall survival (OS) in the entire GeRI cohort (i) All-grade IMC, (iii) Severe IMC. Kaplan–Meier survival curves are unadjusted and compare those who had an IMC (all-grade or severe) with those who did not have an IMC (No IMC). The p-values in the graph represent the log-rank p-values and the dotted line represents median survival time. Graphs are obtained from Cox proportional hazards models with 90-day landmark.