T-cell tolerant fraction as a predictor of immune-related adverse events

BACKGROUND: Immune checkpoint inhibitor (ICI) therapies may cause unpredictable and potentially severe autoimmune toxicities termed immune-related adverse events (irAEs). Because T cells mediate ICI effects, T cell profiling may provide insight into the risk of irAEs. Here we evaluate a novel metric—the T-cell tolerant fraction—as a predictor of future irAEs. METHODS: We examined T-cell receptor beta (TRB) locus sequencing from baseline pretreatment samples from an institutional registry and previously published studies. For each patient, we used TRB sequences to calculate the T-cell tolerant fraction, which was then assessed as a predictor of future irAEs (classified as Common Terminology Criteria for Adverse Event grade 0–1 vs grade ≥2). We then compared the tolerant fraction to TRB clonality and diversity. Finally, the tolerant fraction was assessed on (1) T cells enriched against napsin A, a potential autoantigen of irAEs; (2) thymic versus peripheral blood T cells; and (3) TRBs specific for various infections and autoimmune diseases. RESULTS: A total of 77 patients with cancer (22 from an institutional registry and 55 from published studies) receiving ICI therapy (43 CTLA4, 19 PD1/PDL1, 15 combination CTLA4+PD1/PDL1) were included in the study. The tolerant fraction was significantly lower in cases with clinically significant irAEs (p<0.001) and had an area under the receiver operating curve (AUC) of 0.79. The tolerant fraction was lower for each ICI treatment category, reaching statistical significance for CTLA4 (p<0.001) and demonstrating non-significant trends for PD1/PDL1 (p=0.21) and combination ICI (p=0.18). The tolerant fraction for T cells enriched against napsin A was lower than other samples. The tolerant fraction was also lower in thymic versus peripheral blood samples, and lower in some (multiple sclerosis) but not other (type 1 diabetes) autoimmune diseases. In our study cohort, TRB clonality had an AUC of 0.62, and TRB diversity had an AUC of 0.60 for predicting irAEs. CONCLUSIONS: Among patients receiving ICI, the baseline T-cell tolerant fraction may serve as a predictor of clinically significant irAEs.