Suppressing thymic output prevents systolic impairment in anti-PD-1 therapy
M Kocsis, A Kulin, L Szabo, T Gergely, N V Sayour, V Toth, D Nagy, B Agg, M Szabo, P Ferdinandy, Z V VargaAbstract
Introduction
While immune checkpoint inhibitors (ICIs) have redefined cancer management, however their clinical utility is severely capped by fatal cardiovascular complications. Current consensus attributes this cardiotoxicity exclusively to the dysregulation of peripheral T-cells. We challenge this view by proposing an upstream etiology: the thymus. We propose that anti-PD-1 therapy compromises central tolerance mechanisms, effectively priming the immune system for myocardial injury.
Purpose
We have investigated whether a functional thymus is required for the development of ICI-mediated cardiac dysfunction. Furthermore, we evaluated whether inducing thymic involution through either naturally with biological aging or pharmacologically via 5-Azacytidine (AZA), confers cardioprotection against immunotherapy-induced injury.
Methods
We employed a comparative murine model involving young (12-week) and aged (16-month) C57BL/6J cohorts subjected to anti-PD-1 treatment. To isolate the role of thymic output, we induced pharmacological atrophy in young mice using AZA. Cardiac performance was assessed via high-resolution echocardiography, complemented by myocardial gene expression analysis and deep analysis of thymic and splenic microenvironments via RNAseq, flow cytometry and RNAscope.
Results
Administration of anti-PD-1 precipitated significant systolic impairment in young mice, a cardiotoxic effect that was notably absent in the aged cohort. Mechanistically, young thymuses exhibited profound transcriptional alterations indicative of impaired T-cell selection and regulatory T-cell reduction. In the heart, this resulted in a pro-inflammatory milieu characterized by upregulated Cxcl9, Cxcl10, and Ifng, occurring even in the absence of fulminant myocarditis. Moreover, pharmacological suppression of thymic activity with AZA successfully preserved systolic function and dampened myocardial inflammatory signaling, effectively replicating the protective phenotype observed in aging.
Conclusion
These findings expand the peripheral-centric model of immunotherapy complications, identifying the thymus as a key driver of ICI-induced cardiotoxicity. We demonstrate that anti-PD-1 lowers tolerance thresholds centrally, fueling a heart-specific inflammatory loop. Consequently, thymic activity represents a novel biomarker for cardiovascular risk stratification, and its therapeutic modulation offers a promising new way to decouple potent anti-tumor immunity from life-threatening cardiotoxicity.Graphical abstract