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ORIGINAL RESEARCH article

Front. Mol. Med
Sec. Molecular Medicine for Cardiology
Volume 4 - 2024 | doi: 10.3389/fmmed.2024.1487526
This article is part of the Research Topic Connection between cardiovascular diseases and cancer View all articles

Immune-checkpoint-inhibitor therapy directed against PD-L1 is tolerated in the heart without manifestation of cardiac inflammation in a preclinical reversible melanoma mouse model

Provisionally accepted
Caroline Schoenherr Caroline Schoenherr 1Stefan Pietzsch Stefan Pietzsch 1Cristina Barca Cristina Barca 2Franziska E Müller Franziska E Müller 3Frauke Sophie Bahr Frauke Sophie Bahr 3Martina Kasten Martina Kasten 1Andre Zeug Andre Zeug 3Sergej Erschow Sergej Erschow 1(EE) Christine Susanne Falk (EE) Christine Susanne Falk 4Evgeni Ponimaskin Evgeni Ponimaskin 3James Thomas Thackeray James Thomas Thackeray 2Denise Hilfiker-Kleiner Denise Hilfiker-Kleiner 1Melanie Ricke-Hoch Melanie Ricke-Hoch 1*
  • 1 Department of Cardiology and Angiology, Hannover Medical School, Hanover, Germany
  • 2 Department of Nuclear Medicine, Hannover Medical School, Hanover, Germany
  • 3 Department of Cellular Neurophysiology, Hannover Medical School, Hanover, Germany
  • 4 Institute of Transplant Immunology, IFB-Tx, Hannover Medical School, Hanover, Germany

The final, formatted version of the article will be published soon.

    Immune-checkpoint-inhibitors (ICI) target key regulators of the immune system expressed by cancer cells that mask those from recognition by the immune system. They have improved the outcome for patients with various cancer types, such as melanoma. ICI-based therapy is frequently accompanied by immune-related adverse side effects (IRAEs). The reversible melanoma cancer mouse model (B16F10 cells stably expressing a ganciclovir (GCV)-inducible suicide gene in C57BL/6N mice: B16F10-GCV) allows chemotherapy-free tumor elimination in advanced disease stage and demonstrates almost complete recovery of the mouse heart from cancer-induced atrophy, molecular impairment and heart failure. Thus, enabling the study of anti-cancer-therapy effects. Here, we analyzed potential cardiac side effects of antibody-mediated PD-L1 inhibition in the preclinical B16F10-GCV mouse model after tumor elimination and two weeks recovery (50 days after tumor inoculation). Anti-PD-L1 treatment was associated with improved survival as compared to isotype control (Ctrl) treated mice. Surviving anti-PD-L1 and Ctrl mice showed similar cardiac function, dimensions and the expression of cardiac stress and hypertrophy markers. Although anti-PD-L1 treatment was associated with increased troponin I type 3 cardiac (TNNI3) blood levels, cardiac mRNA expression of macrophage markers and elevated cardiac levels of secreted inflammatory factors compared to Ctrl treatment, both groups showed a comparable density of inflammatory cells in the heart (using CXCR4-ligand 68Ga-Pentixafor in PET-CT and immunohistochemistry). Thus, anti-PD-L1 therapy improved survival in mice with advanced melanoma cancer with no major cardiac phenotype or inflammation 50 days after tumor inoculation. Without a second hit that triggers the inflammatory response, anti-PD-L1 treatment appears to be safe for the heart in the preclinical melanoma mouse model.

    Keywords: immune checkpoint inhibitors, PD-L1, Inflammation, Cancer, Cardio-oncology, cardiotoxicity

    Received: 28 Aug 2024; Accepted: 10 Dec 2024.

    Copyright: © 2024 Schoenherr, Pietzsch, Barca, Müller, Bahr, Kasten, Zeug, Erschow, Falk, Ponimaskin, Thackeray, Hilfiker-Kleiner and Ricke-Hoch. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

    * Correspondence: Melanie Ricke-Hoch, Department of Cardiology and Angiology, Hannover Medical School, Hanover, Germany

    Disclaimer: All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article or claim that may be made by its manufacturer is not guaranteed or endorsed by the publisher.