Immune profiling to identify predictive biomarkers and highlights the potential efficacy of IL-6R blockade in checkpoint inhibitor–related myocarditis.

Abstract

12118 Background: Immune checkpoint inhibitor–associated myocarditis (ICI-My) is a rare but potentially life-threatening complication. Advancing our understanding of its underlying immunological mechanisms is essential for the development of improved diagnostic tools and treatment strategies, with the aim of minimizing morbidity and mortality. Methods: This retrospective single-center study (July 2019–June 2024) identified 33 patients who developed ICI-My. A Comprehensive immuno-profiling was conducted using 49 cytokines, 7 traditional cardiac biomarkers, and 46 mass cytometry markers. These profiles were compared to the baseline levels of a cohort of 97 cancer patients prior to ICI treatment. The analysis assessed the identification of biomarkers for differentiating low and high-grade myocarditis and corticosteroids (CS)-refractory ICI-My. The therapeutic efficacy of tocilizumab was assessed in eight cases of CS-refractory myocarditis. Results: ICI-My patients showed marked elevations in IL-6, CXCL9, CXCL10, CXCL13, VEGF-A, and sCD25 compared with baseline cancer patients prior to ICI initiation. High-grade myocarditis was characterized by lower levels of CCL4 and CXCL12, with predictive accuracies of 78.6% and 82.1%, respectively. In contrast, conventional biomarkers (cTnT, cTnI, CK, CK-MB, NT-ProBNP, and d-dimers) failed to differentiate disease severity. Mass cytometry revealed a distinct immune profile in ICI-My, including increased immature neutrophils, reduced switched and unswitched memory B cells, elevated double-positive (CD38⁺/HLA-DR⁺) T cells across CD4⁺ and CD8⁺ subsets, decreased CXCR5⁺ leukocytes, and diminished CXCR3 expression within all memory T-cell subsets. Notably, no complement activation was detected. HGF, CXCL10, and BDNF successfully discriminated patients requiring immunosuppression from those untreated (accuracies of 89%, 79%, and 79%, respectively), while IL-18 and CCL4 predicted the need for tocilizumab (TCZ) therapy (accuracies of 79% and 82%, respectively). This underscores the dual benefit of CCL4. In addition, all cases of corticosteroid (CS)-refractory myocarditis (n = 8), including those unresponsive to mycophenolate mofetil or infliximab, responded effectively to TCZ. Conclusions: This study provides the first comprehensive immuno-profile of ICI-My. CCL4 and CXCL12 outperformed some traditional cardiac biomarkers as prognostic tools, while IL-18 and CCL4 emerged as key predictors for tocilizumab therapy, which could offer a personalized therapeutic approach. The absence of complement activation indicates that cytokine-mediated and cellular pathways are central to ICI-My pathogenesis. Notably, the success of anti-IL-6 therapy in CS-refractory cases highlights new therapeutic opportunities, enhancing patient care and guiding future interventions.