Document Type

Article

Publication Date

5-28-2026

Comments

This article is the author’s final published version in Journal for immunotherapy of cancer, Volume 14, Issue 5, 2026.

The published version is available at https://doi.org/10.1136/jitc-2025-014290. Copyright ©  Author(s) (or their employer(s)) 2026.

Abstract

BACKGROUND: Immune checkpoint inhibitor-associated myocarditis (ICIAM) poses significant challenges for cancer immunotherapy, particularly regarding the safety and efficacy of immune checkpoint blockade (ICB) rechallenge.

METHODS: The present study analyzed 23 cases of ICIAM by integrating longitudinal clinical data with single-cell RNA sequencing and T-cell receptor profiling of peripheral blood mononuclear cells (PBMCs) obtained from three representative patients before and after ICB rechallenge. The single-cell cohort comprised two patients who experienced recurrent irAEs upon rechallenge and one patient who did not develop recurrent irAEs.

RESULTS: Among 12 patients (52%) who experienced recurrent irAEs upon rechallenge, myocarditis recurrence occurred in 8 cases, with most (88%) presenting as grade 1— significantly milder than initial episodes (p=0.046). Single- cell analysis revealed that the patient who did not develop recurrent irAEs exhibited a high proportion of effector CD8+ T cells with high TRAV19 expression (CD8 Teff TRAV19), a TCR Vα family associated with SARS- CoV- 2 reactivity. In contrast, patients who experienced recurrent irAEs lacked this expanded population. Rechallenge during myocarditis course was associated with higher recurrent irAEs risk (OR=14.0, 95%CI:1.3- 147.4, p=0.027). Despite recurrence, tumor response was preserved, with a median progression- free survival (mPFS) of 8.5 months and no significant outcome difference between patients with and without post- rechallenge irAEs.

CONCLUSION: ICB rechallenge is feasible in selected ICIAM patients, with most recurrent myocarditis cases being milder. Our exploratory single-cell analysis reveals that a high proportion of CD8 Teff TRAV19 was present in the patient protected from recurrence but absent in those who relapsed, suggesting that pre-existing virus specific memory T cells may modulate recurrent irAEs risk via antigen-specific niche occupation. While limited by sample size, these findings generate the hypothesis that T-cell repertoire composition could inform patient selection for ICB rechallenge, a concept warranting validation in larger cohorts.

Creative Commons License

Creative Commons License
This work is licensed under a Creative Commons Attribution-Noncommercial 4.0 License

PubMed ID

42208979

Language

English

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