Immune checkpoint inhibitors reverse tolerogenic mechanisms induced by melanoma targeted radionuclide therapy
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ORIGINAL ARTICLE
Immune checkpoint inhibitors reverse tolerogenic mechanisms induced by melanoma targeted radionuclide therapy Jacques Rouanet1,2,3 · Valentin Benboubker1,4 · Hussein Akil1 · Ana Hennino5 · Philippe Auzeloux1 · Sophie Besse1 · Bruno Pereira6 · Solène Delorme1 · Sandrine Mansard2 · Michel D’Incan1,2 · Françoise Degoul1 · Paul‑Olivier Rouzaire1,4 Received: 3 February 2020 / Accepted: 12 May 2020 © Springer-Verlag GmbH Germany, part of Springer Nature 2020
Abstract In line with the ongoing phase I trial (NCT03784625) dedicated to melanoma targeted radionuclide therapy (TRT), we explore the interplay between immune system and the melanin ligand [131I]ICF01012 alone or combined with immunotherapy (immune checkpoint inhibitors, ICI) in preclinical models. Here we demonstrate that [ 131I]ICF01012 induces immunogenic cell death, characterized by a significant increase in cell surface-exposed annexin A1 and calreticulin. Additionally, [131I] ICF01012 increases survival in immunocompetent mice, compared to immunocompromised (29 vs. 24 days, p = 0.0374). Flow cytometry and RT-qPCR analyses highlight that [ 131I]ICF01012 induces adaptive and innate immune cell recruitment in the tumor microenvironment. [131I]ICF01012 combination with ICIs (anti-CTLA-4, anti-PD-1, anti-PD-L1) has shown that tolerance is a main immune escape mechanism, whereas exhaustion is not present after TRT. Furthermore, [131I]ICF01012 and ICI combination has systematically resulted in a prolonged survival (p
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