TY - JOUR
T1 - T-cell tolerant fraction as a predictor of immune-related adverse events
AU - Ostmeyer, Jared
AU - Park, Jason Y.
AU - Von Itzstein, Mitchell S.
AU - Hsiehchen, David
AU - Fattah, Farjana
AU - Gwin, Mary
AU - Catalan, Rodrigo
AU - Khan, Shaheen
AU - Raj, Prithvi
AU - Wakeland, Edward K.
AU - Xie, Yang
AU - Gerber, David E.
N1 - Publisher Copyright:
© 2023 Author(s). Published by BMJ.
PY - 2023/8/13
Y1 - 2023/8/13
N2 - 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.
AB - 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.
KW - Autoimmunity
KW - Immune Tolerance
KW - Immunotherapy
KW - T-Lymphocytes
KW - Translational Medical Research
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U2 - 10.1136/jitc-2022-006437
DO - 10.1136/jitc-2022-006437
M3 - Article
C2 - 37580069
AN - SCOPUS:85168191163
SN - 2051-1426
VL - 11
JO - Journal for ImmunoTherapy of Cancer
JF - Journal for ImmunoTherapy of Cancer
IS - 8
M1 - e006437
ER -