AHA Scientific Sessions 2026 Abstract · Nov 2, 2026
Single-Cell Genomics Uncovers a Female-Predominant JAK-STAT Inflammatory Signature in Immune Checkpoint Inhibitor Myocarditis and Nominates Sex-Tailored Cardioprotection
By Manchanda N, Smith N, Villani AC et al.
Background: Immune checkpoint inhibitor (ICI)-associated myocarditis affects 1-2% of ICI treated patients but is the most lethal immune-related adverse event (mortality up to 50%). Women are underrepresented in mechanistic studies in ICI myocarditis despite evidence of heightened immune activation in women. Prior studies have shown differential pathways affecting males vs females in viral myocarditis, with implications for differential strategies for therapeutic interventions. It is unclear whether there are sex specific differences in ICI myocarditis. Additionally, clonal hematopoiesis of indeterminate potential (CHIP) is a non-traditional driver of cardiovascular risk and ICI myocarditis. No study has resolved how sex and CHIP jointly shape ICI-myocarditis immune circuitry at single-cell resolution in humans. Hypothesis: We hypothesized that women with ICI-myocarditis mount a distinct inflammatory response, amplified by CHIP and converging on druggable axes such as JAK-STAT. We mapped sex- and CHIP-resolved immune pathway activity in circulating immune cells to nominate female-tailored interventions. Methods: We analyzed PBMC single-cell RNA-seq from Yale (CHIP+ 26k/22k male/female cells; CHIP- 60k/12k) and MGH (CHIP+ 82k/6k; CHIP- 93k/31k) post-ICI myocarditis cohorts. Integration used scVI/Scanpy; cells were annotated with ScType and validated by markers; gene-set activity was scored with AUCell. Sex differences were quantified as the median AUC effect size (Δ) between female and male patients (Wilcoxon, FDR < 0.05; Table 1 ). Results: In MGH CHIP+, women showed marked elevation (FDR < 0.05) of interferon-driven signaling: JAK-STAT (Δ > 0.01), TNF (Δ > 0.01), IL-17 (Δ > 0.004), and Th1/Th2 (Δ > 0.004), across myeloid and lymphoid cells. The Yale CHIP+ response was restrained, with female JAK-STAT (Δ > 0.05) confined to platelets, matching our prior platelet-activation finding ( Table 1 ). In CHIP- patients, women showed elevated JAK-STAT (Δ > 0.003) and Th1/Th2 (Δ > 0.001) with antigen-driven autoimmune cascades KIR-HLA and MYH-ACT ( Figure 1 ). This consistent convergence on JAK-STAT, targetable by available JAK inhibitors, defines a sex-specific, actionable mechanism. Conclusion: At single-cell resolution in humans, we identify a female-predominant, CHIP-amplified inflammatory architecture in ICI-myocarditis converging on the druggable JAK-STAT pathway. These data support sex-informed immunomodulation (e.g., JAK inhibition) and deliberate enrollment of women in ICI-myocarditis trials.