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MAPK inhibitors dynamically affect melanoma release of immune NKG2D-ligands, as soluble protein and extracellular vesicle-associated

Metastatic melanoma presents, in many cases, oncogenic mutations in BRAF, a MAPK involved in proliferation of tumour cells. BRAF inhibitors, used as therapy in patients with these mutations, often lead to tumour resistance and, thus, the use of MEK inhibitors was introduced in clinics. BRAFi/MEKi, a...

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Autores principales: López-Borrego, Silvia, Campos-Silva, Carmen, Sandúa, Amaia, Camino, Tamara, Téllez-Pérez, Lucía, Alegre, Estibaliz, Beneitez, Alexandra, Jara-Acevedo, Ricardo, Paschen, Annette, Pardo, María, González, Álvaro, Valés-Gómez, Mar
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Frontiers Media S.A. 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9884675/
https://www.ncbi.nlm.nih.gov/pubmed/36726591
http://dx.doi.org/10.3389/fcell.2022.1055288
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author López-Borrego, Silvia
Campos-Silva, Carmen
Sandúa, Amaia
Camino, Tamara
Téllez-Pérez, Lucía
Alegre, Estibaliz
Beneitez, Alexandra
Jara-Acevedo, Ricardo
Paschen, Annette
Pardo, María
González, Álvaro
Valés-Gómez, Mar
author_facet López-Borrego, Silvia
Campos-Silva, Carmen
Sandúa, Amaia
Camino, Tamara
Téllez-Pérez, Lucía
Alegre, Estibaliz
Beneitez, Alexandra
Jara-Acevedo, Ricardo
Paschen, Annette
Pardo, María
González, Álvaro
Valés-Gómez, Mar
author_sort López-Borrego, Silvia
collection PubMed
description Metastatic melanoma presents, in many cases, oncogenic mutations in BRAF, a MAPK involved in proliferation of tumour cells. BRAF inhibitors, used as therapy in patients with these mutations, often lead to tumour resistance and, thus, the use of MEK inhibitors was introduced in clinics. BRAFi/MEKi, a combination that has modestly increased overall survival in patients, has been proven to differentially affect immune ligands, such as NKG2D-ligands, in drug-sensitive vs. drug-resistant cells. However, the fact that NKG2D-ligands can be released as soluble molecules or in extracellular vesicles represents an additional level of complexity that has not been explored. Here we demonstrate that inhibition of MAPK using MEKi, and the combination of BRAFi with MEKi in vitro, modulates NKG2D-ligands in BRAF-mutant and WT melanoma cells, together with other NK activating ligands. These observations reinforce a role of the immune system in the generation of resistance to directed therapies and support the potential benefit of MAPK inhibition in combination with immunotherapies. Both soluble and EV-associated NKG2D-ligands, generally decreased in BRAF-mutant melanoma cell supernatants after MAPKi in vitro, replicating cell surface expression. Because potential NKG2D-ligand fluctuation during MAPKi treatment could have different consequences for the immune response, a pilot study to measure NKG2D-ligand variation in plasma or serum from metastatic melanoma patients, at different time points during MAPKi treatment, was performed. Not all NKG2D-ligands were equally detected. Further, EV detection did not parallel soluble protein. Altogether, our data confirm the heterogeneity between melanoma lesions, and suggest testing several NKG2D-ligands and other melanoma antigens in serum, both as soluble or vesicle-released proteins, to help classifying immune competence of patients.
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spelling pubmed-98846752023-01-31 MAPK inhibitors dynamically affect melanoma release of immune NKG2D-ligands, as soluble protein and extracellular vesicle-associated López-Borrego, Silvia Campos-Silva, Carmen Sandúa, Amaia Camino, Tamara Téllez-Pérez, Lucía Alegre, Estibaliz Beneitez, Alexandra Jara-Acevedo, Ricardo Paschen, Annette Pardo, María González, Álvaro Valés-Gómez, Mar Front Cell Dev Biol Cell and Developmental Biology Metastatic melanoma presents, in many cases, oncogenic mutations in BRAF, a MAPK involved in proliferation of tumour cells. BRAF inhibitors, used as therapy in patients with these mutations, often lead to tumour resistance and, thus, the use of MEK inhibitors was introduced in clinics. BRAFi/MEKi, a combination that has modestly increased overall survival in patients, has been proven to differentially affect immune ligands, such as NKG2D-ligands, in drug-sensitive vs. drug-resistant cells. However, the fact that NKG2D-ligands can be released as soluble molecules or in extracellular vesicles represents an additional level of complexity that has not been explored. Here we demonstrate that inhibition of MAPK using MEKi, and the combination of BRAFi with MEKi in vitro, modulates NKG2D-ligands in BRAF-mutant and WT melanoma cells, together with other NK activating ligands. These observations reinforce a role of the immune system in the generation of resistance to directed therapies and support the potential benefit of MAPK inhibition in combination with immunotherapies. Both soluble and EV-associated NKG2D-ligands, generally decreased in BRAF-mutant melanoma cell supernatants after MAPKi in vitro, replicating cell surface expression. Because potential NKG2D-ligand fluctuation during MAPKi treatment could have different consequences for the immune response, a pilot study to measure NKG2D-ligand variation in plasma or serum from metastatic melanoma patients, at different time points during MAPKi treatment, was performed. Not all NKG2D-ligands were equally detected. Further, EV detection did not parallel soluble protein. Altogether, our data confirm the heterogeneity between melanoma lesions, and suggest testing several NKG2D-ligands and other melanoma antigens in serum, both as soluble or vesicle-released proteins, to help classifying immune competence of patients. Frontiers Media S.A. 2023-01-16 /pmc/articles/PMC9884675/ /pubmed/36726591 http://dx.doi.org/10.3389/fcell.2022.1055288 Text en Copyright © 2023 López-Borrego, Campos-Silva, Sandúa, Camino, Téllez-Pérez, Alegre, Beneitez, Jara-Acevedo, Paschen, Pardo, González and Valés-Gómez. https://creativecommons.org/licenses/by/4.0/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) and the copyright owner(s) 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.
spellingShingle Cell and Developmental Biology
López-Borrego, Silvia
Campos-Silva, Carmen
Sandúa, Amaia
Camino, Tamara
Téllez-Pérez, Lucía
Alegre, Estibaliz
Beneitez, Alexandra
Jara-Acevedo, Ricardo
Paschen, Annette
Pardo, María
González, Álvaro
Valés-Gómez, Mar
MAPK inhibitors dynamically affect melanoma release of immune NKG2D-ligands, as soluble protein and extracellular vesicle-associated
title MAPK inhibitors dynamically affect melanoma release of immune NKG2D-ligands, as soluble protein and extracellular vesicle-associated
title_full MAPK inhibitors dynamically affect melanoma release of immune NKG2D-ligands, as soluble protein and extracellular vesicle-associated
title_fullStr MAPK inhibitors dynamically affect melanoma release of immune NKG2D-ligands, as soluble protein and extracellular vesicle-associated
title_full_unstemmed MAPK inhibitors dynamically affect melanoma release of immune NKG2D-ligands, as soluble protein and extracellular vesicle-associated
title_short MAPK inhibitors dynamically affect melanoma release of immune NKG2D-ligands, as soluble protein and extracellular vesicle-associated
title_sort mapk inhibitors dynamically affect melanoma release of immune nkg2d-ligands, as soluble protein and extracellular vesicle-associated
topic Cell and Developmental Biology
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9884675/
https://www.ncbi.nlm.nih.gov/pubmed/36726591
http://dx.doi.org/10.3389/fcell.2022.1055288
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