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Immune checkpoint inhibitors reverse tolerogenic mechanisms induced by melanoma targeted radionuclide therapy

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 < 0.0001) compared to TRT alone. Specifically, [131I]ICF01012 + anti-CTLA-4 combination significantly increases survival compared to anti-CTLA-4 alone (41 vs. 26 days; p = 0.0011), without toxicity. This work represents the first global characterization of TRT-induced modifications of the antitumor immune response, demonstrating that tolerance is a main immune escape mechanism and that combining TRT and ICI is promising.

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Abbreviations

Ab:

Antibody

DAMPs:

Damage-associated molecular pattern molecules

EBRT:

External beam radiation therapy

ICI:

Immune checkpoint inhibitors

NK:

Natural killer

TRT:

Targeted radionuclide therapy

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Acknowledgements

We are grateful to C.VACCHIAS from confocal imaging platform (CLIC) and to C.SOUBEYRAND-DAMON from histopathology platform (ANIPATH) for their pertinent advices. We thank M.GEMBARA for his kind proofreading of the English manuscript.

Funding

This study was supported by the SFD – French Society for Dermatology and by the Ligue Régionale Contre le Cancer. J. ROUANET is supported by a doctoral fellowship granted by the SFD. H. AKIL was supported by a fellowship from the Auvergne Regional council and the European Community. A. Hennino is supported by INSERM TRANSFERT, Fondation Bristol-Meyers Squibb and La Ligue Régionale Contre le Cancer.

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Authors

Contributions

JR, AH, SM, MD, FD and POR contributed to the study conception and design. Material preparation, data collection and analysis were performed by JR, VB, HA, SB, PA and SD. BP performed statistical analyses. The first draft of the manuscript was written by JR, and all authors commented on previous versions of the manuscript. All authors read and approved the final manuscript.

Corresponding author

Correspondence to Jacques Rouanet.

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The authors declare that they have no conflict of interest.

Ethics approval

Experimentations on mice were in conformity with the Guide for the Care and Use of Laboratory Animals published by the US National Institutes of Health (8th edition, 2011) and were approved by local Ethic committee of Clermont-Ferrand (C2E2A No. 002) and French Ministry of Education and Research (Approval No. 12211). This article does not contain any studies with human participants performed by any of the authors.

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Rouanet, J., Benboubker, V., Akil, H. et al. Immune checkpoint inhibitors reverse tolerogenic mechanisms induced by melanoma targeted radionuclide therapy. Cancer Immunol Immunother 69, 2075–2088 (2020). https://doi.org/10.1007/s00262-020-02606-8

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  • DOI: https://doi.org/10.1007/s00262-020-02606-8

Keywords

  • Targeted radionuclide therapy
  • Metastatic melanoma
  • Immune checkpoint inhibitor
  • Tolerance
  • Melanin
  • Anti-βig-h3