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Journal of Experimental & Clinical Cancer Research

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Open Access 01-12-2021 | Melanoma | Research

MITF induces escape from innate immunity in melanoma

Authors: Luis Sánchez-del-Campo, Román Martí-Díaz, María F. Montenegro, Rebeca González-Guerrero, Trinidad Hernández-Caselles, Enrique Martínez-Barba, Antonio Piñero-Madrona, Juan Cabezas-Herrera, Colin R. Goding, José Neptuno Rodríguez-López

Published in: Journal of Experimental & Clinical Cancer Research | Issue 1/2021

Abstract

Background

The application of immune-based therapies has revolutionized cancer treatment. Yet how the immune system responds to phenotypically heterogeneous populations within tumors is poorly understood. In melanoma, one of the major determinants of phenotypic identity is the lineage survival oncogene MITF that integrates diverse microenvironmental cues to coordinate melanoma survival, senescence bypass, differentiation, proliferation, invasion, metabolism and DNA damage repair. Whether MITF also controls the immune response is unknown.

Methods

By using several mouse melanoma models, we examine the potential role of MITF to modulate the anti-melanoma immune response. ChIP-seq data analysis, ChIP-qPCR, CRISPR-Cas9 genome editing, and luciferase reporter assays were utilized to identify ADAM10 as a direct MITF target gene. Western blotting, confocal microscopy, flow cytometry, and natural killer (NK) cytotoxicity assays were used to determine the underlying mechanisms by which MITF-driven phenotypic plasticity modulates melanoma NK cell-mediated killing.

Results

Here we show that MITF regulates expression of ADAM10, a key sheddase that cleaves the MICA/B family of ligands for NK cells. By controlling melanoma recognition by NK-cells MITF thereby controls the melanoma response to the innate immune system. Consequently, while melanoma MITF^Low cells can be effectively suppressed by NK-mediated killing, MITF-expressing cells escape NK cell surveillance.

Conclusion

Our results reveal how modulation of MITF activity can impact the anti-melanoma immune response with implications for the application of anti-melanoma immunotherapies.

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Title: MITF induces escape from innate immunity in melanoma
Authors: Luis Sánchez-del-Campo
Román Martí-Díaz
María F. Montenegro
Rebeca González-Guerrero
Trinidad Hernández-Caselles
Enrique Martínez-Barba
Antonio Piñero-Madrona
Juan Cabezas-Herrera
Colin R. Goding
José Neptuno Rodríguez-López
Publication date: 01-12-2021
Publisher: BioMed Central
Keywords: Melanoma
Melanoma
Published in: Journal of Experimental & Clinical Cancer Research / Issue 1/2021
Electronic ISSN: 1756-9966
DOI: https://doi.org/10.1186/s13046-021-01916-8

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