Douglas Daoudlarian, Sarah Boughdad, Robin Bartolini, Sofiya Latifyan, Jacqueline Doms, Hasna Bouchaab, Karim Abdelhamid, Nabila Ferahta, N.N. Mederos Alfonso, Victor Joo, Antonia Stamatiou, Lucrezia Mencarelli, Nicolas Etienne, Athina Stravodimou, Khalil Zaman, Matthieu Perreau, Craig Fenwick, Keyvan Shabafrouz, Giuseppe Pantaleo, Solange Peters, Michel Obéid
BACKGROUND: Immune checkpoint inhibitor-associated myocarditis (ICI-My) is rare but potentially life-threatening. Biomarkers that distinguish myocarditis-related inflammation from background immune activation induced by ICIs remain needed. OBJECTIVES: This study sought to define the circulating inflammatory and cellular immune landscape of ICI-My, relate these findings to clinical severity, and explore the feasibility of interleukin-6 receptor (IL-6R) blockade in selected steroid-refractory cases. METHODS: In this single-center retrospective cohort (January 2018 to June 2024), we performed biomarker profiling including multiplex cytokine profiling in 33 patients with ICI-My (7 severe and 26 nonsevere, 28 cytokines profiles) and 68 ICI-treated patients without myocarditis or other immune-related adverse events. Mass cytometry analyses compared 16 patients with ICI-My with 72 ICI-treated patients without myocarditis or other immune-related adverse events. We also describe eight steroid-refractory patients treated with tocilizumab on a compassionate-use basis. RESULTS: memory B- and T-cell populations, contraction of switched and unswitched memory B-cell compartments, and lower CXCR3 expression across memory T-cell subsets. No clear systemic complement activation signal was observed. High-sensitivity troponin T, N-terminal pro-B-type natriuretic peptide, aspartate aminotransferase, and alanine aminotransferase discriminated severe from nonsevere myocarditis more consistently than individual cytokines. In eight steroid-refractory cases, tocilizumab administration was feasible, but this uncontrolled series cannot establish efficacy. CONCLUSIONS: Peripheral immune profiling identifies an IL-6-centered and chemokine-centered inflammatory signature in ICI-My beyond background ICI exposure. Conventional cardiac biomarkers remain more informative than single cytokines for severity assessment in this cohort. IL-6R blockade appears biologically plausible and clinically feasible in selected steroid-refractory cases and warrants prospective evaluation.