Activation specific CD11b inhibition mitigates immune checkpoint inhibitor associated cardiac and intestinal toxicity while preserving anti tumor effects
I Bojti, A Ziegler, S Bojtne Kovacs, L Braun, N Jung, T Marchini, X Li, D Westermann, D WolfAbstract
Background
Immune checkpoint inhibitors (ICI) can induce myocarditis and colitis through excessive immune activation and myeloid-dependent tissue infiltration. Current treatment strategies rely on broad immunosuppression and may compromise anti-tumor immunity. We hypothesized that selective inhibition of activated CD11b (Mac-1) would limit pathogenic immune cell trafficking while preserving systemic T-cell responses and anti-tumor efficacy.
Methods
ICI toxicity was induced in wild-type mice using anti-PD-1 therapy. Mice were treated with Neutrophil Inhibitory Factor (NIF), an activation-specific CD11b inhibitor, or vehicle control. Cardiac injury was assessed by serum troponin and echocardiographic left ventricular ejection fraction (LVEF). Cardiac immune infiltrates were quantified by flow cytometry. Systemic cytokine profiles were assessed in serum using LEGENDplex bead-based multiplex assays. Colonic injury was evaluated by histological damage scoring on hematoxylin and eosin (H&E)-stained sections. CD11b-dependent adhesion was tested in vitro using ICAM-1-coated plates. To assess anti-tumor efficacy, a B16.F10 melanoma model was employed, and tumor progression was compared between anti-PD-1–treated mice with or without concomitant NIF administration.
Results
NIF treatment significantly reduced serum troponin levels and preserved LVEF compared with vehicle controls. Flow cytometric analysis of cardiac tissue demonstrated a marked and highly significant reduction of Ly6C^high monocytes, indicating effective blockade of activated myeloid cell infiltration, while absolute CD8⁺ T-cell numbers were not reduced. H&E analysis of colonic tissue revealed significantly less histological damage in NIF-treated mice compared with controls. LEGENDplex analysis demonstrated altered systemic cytokine profiles consistent with reduced tissue injury. In vitro, NIF dose-dependently inhibited CD11b–ICAM-1–mediated adhesion. Importantly, in the B16.F10 melanoma model, concomitant NIF treatment did not impair the anti-tumor efficacy of anti-PD-1 therapy, as tumor progression was comparable to anti-PD-1 treatment alone.
Conclusions
Activation-specific CD11b inhibition with NIF selectively blocks pathogenic Ly6C^high monocyte infiltration during ICI therapy, preserving cardiac function and reducing colonic tissue injury while sparing CD8⁺ T-cell abundance. Importantly, this protective effect does not compromise anti-tumor efficacy. Targeted CD11b inhibition therefore represents a precision strategy to mitigate ICI-associated toxicity without broad immunosuppression