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

• Published in: Cancer Immunology, Immunotherapy Vol. 69; no. 10; pp. 2075 - 2088
• Main Authors: Rouanet, Jacques, Benboubker, Valentin, Akil, Hussein, Hennino, Ana, Auzeloux, Philippe, Besse, Sophie, Pereira, Bruno, Delorme, Solène, Mansard, Sandrine, D’Incan, Michel, Degoul, Françoise, Rouzaire, Paul-Olivier
• Format: Journal Article
• Language: English
• Published: Berlin/Heidelberg Springer Berlin Heidelberg 01.10.2020; Springer Nature B.V; Springer Verlag
• Subjects: Animals; Antineoplastic Agents, Immunological - therapeutic use; Antitumor activity; Calreticulin; Cancer; Cancer Research; Cell death; Cell surface; Combined Modality Therapy; CTLA-4 protein; Flow cytometry; Immune checkpoint inhibitors; Immune evasion; Immune response; Immunogenicity; Immunological tolerance; Immunology; Immunotherapy; Immunotherapy - methods; Iodine Radioisotopes - therapeutic use; Life Sciences; Medicine; Medicine & Public Health; Melanin; Melanoma; Melanoma, Experimental - immunology; Melanoma, Experimental - pathology; Melanoma, Experimental - therapy; Mice; Oncology; Original; Original Article; PD-1 protein; PD-L1 protein; Radiation therapy; Radiation Tolerance - drug effects; Toxicity; Tumor Cells, Cultured; Tumor microenvironment; Tumor Protein, Translationally-Controlled 1; Tolerance; Targeted radionuclide therapy; Metastatic melanoma; Immune checkpoint inhibitor; Anti-βig-h3; Melanin
• ISSN: 0340-7004; 1432-0851; 1432-0851
• DOI: 10.1007/s00262-020-02606-8

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 [ 131 I]ICF01012 alone or combined with immunotherapy (immune checkpoint inhibitors, ICI) in preclinical models. Here we demonstrate that [ 131 I]ICF01012 induces immunogenic cell death, characterized by a significant increase in cell surface-exposed annexin A1 and calreticulin. Additionally, [ 131 I]ICF01012 increases survival in immunocompetent mice, compared to immunocompromised (29 vs. 24 days, p  = 0.0374). Flow cytometry and RT-qPCR analyses highlight that [ 131 I]ICF01012 induces adaptive and innate immune cell recruitment in the tumor microenvironment. [ 131 I]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, [ 131 I]ICF01012 and ICI combination has systematically resulted in a prolonged survival ( p  < 0.0001) compared to TRT alone. Specifically, [ 131 I]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.