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MEK inhibition enhances presentation of targetable MHC-I tumor antigens in mutant melanomas

Combining multiple therapeutic strategies in NRAS/BRAF mutant melanoma—namely MEK/BRAF kinase inhibitors, immune checkpoint inhibitors (ICIs), and targeted immunotherapies—may offer an improved survival benefit by overcoming limitations associated with any individual therapy. Still, optimal combinat...

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Autores principales: Stopfer, Lauren E., Rettko, Nicholas J., Leddy, Owen, Mesfin, Joshua M., Brown, Eric, Winski, Shannon, Bryson, Bryan, Wells, James A., White, Forest M.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: National Academy of Sciences 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9894220/
https://www.ncbi.nlm.nih.gov/pubmed/36454758
http://dx.doi.org/10.1073/pnas.2208900119
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author Stopfer, Lauren E.
Rettko, Nicholas J.
Leddy, Owen
Mesfin, Joshua M.
Brown, Eric
Winski, Shannon
Bryson, Bryan
Wells, James A.
White, Forest M.
author_facet Stopfer, Lauren E.
Rettko, Nicholas J.
Leddy, Owen
Mesfin, Joshua M.
Brown, Eric
Winski, Shannon
Bryson, Bryan
Wells, James A.
White, Forest M.
author_sort Stopfer, Lauren E.
collection PubMed
description Combining multiple therapeutic strategies in NRAS/BRAF mutant melanoma—namely MEK/BRAF kinase inhibitors, immune checkpoint inhibitors (ICIs), and targeted immunotherapies—may offer an improved survival benefit by overcoming limitations associated with any individual therapy. Still, optimal combination, order, and timing of administration remains under investigation. Here, we measure how MEK inhibition (MEKi) alters anti-tumor immunity by utilizing quantitative immunopeptidomics to profile changes in the peptide major histocompatibility molecules (pMHC) repertoire. These data reveal a collection of tumor antigens whose presentation levels are selectively augmented following therapy, including several epitopes present at over 1,000 copies per cell. We leveraged the tunable abundance of MEKi-modulated antigens by targeting four epitopes with pMHC-specific T cell engagers and antibody drug conjugates, enhancing cell killing in tumor cells following MEK inhibition. These results highlight drug treatment as a means to enhance immunotherapy efficacy by targeting specific upregulated pMHCs and provide a methodological framework for identifying, quantifying, and therapeutically targeting additional epitopes of interest.
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spelling pubmed-98942202023-02-03 MEK inhibition enhances presentation of targetable MHC-I tumor antigens in mutant melanomas Stopfer, Lauren E. Rettko, Nicholas J. Leddy, Owen Mesfin, Joshua M. Brown, Eric Winski, Shannon Bryson, Bryan Wells, James A. White, Forest M. Proc Natl Acad Sci U S A Biological Sciences Combining multiple therapeutic strategies in NRAS/BRAF mutant melanoma—namely MEK/BRAF kinase inhibitors, immune checkpoint inhibitors (ICIs), and targeted immunotherapies—may offer an improved survival benefit by overcoming limitations associated with any individual therapy. Still, optimal combination, order, and timing of administration remains under investigation. Here, we measure how MEK inhibition (MEKi) alters anti-tumor immunity by utilizing quantitative immunopeptidomics to profile changes in the peptide major histocompatibility molecules (pMHC) repertoire. These data reveal a collection of tumor antigens whose presentation levels are selectively augmented following therapy, including several epitopes present at over 1,000 copies per cell. We leveraged the tunable abundance of MEKi-modulated antigens by targeting four epitopes with pMHC-specific T cell engagers and antibody drug conjugates, enhancing cell killing in tumor cells following MEK inhibition. These results highlight drug treatment as a means to enhance immunotherapy efficacy by targeting specific upregulated pMHCs and provide a methodological framework for identifying, quantifying, and therapeutically targeting additional epitopes of interest. National Academy of Sciences 2022-12-01 2022-12-06 /pmc/articles/PMC9894220/ /pubmed/36454758 http://dx.doi.org/10.1073/pnas.2208900119 Text en Copyright © 2022 the Author(s). Published by PNAS. https://creativecommons.org/licenses/by-nc-nd/4.0/This open access article is distributed under Creative Commons Attribution-NonCommercial-NoDerivatives License 4.0 (CC BY-NC-ND) (https://creativecommons.org/licenses/by-nc-nd/4.0/) .
spellingShingle Biological Sciences
Stopfer, Lauren E.
Rettko, Nicholas J.
Leddy, Owen
Mesfin, Joshua M.
Brown, Eric
Winski, Shannon
Bryson, Bryan
Wells, James A.
White, Forest M.
MEK inhibition enhances presentation of targetable MHC-I tumor antigens in mutant melanomas
title MEK inhibition enhances presentation of targetable MHC-I tumor antigens in mutant melanomas
title_full MEK inhibition enhances presentation of targetable MHC-I tumor antigens in mutant melanomas
title_fullStr MEK inhibition enhances presentation of targetable MHC-I tumor antigens in mutant melanomas
title_full_unstemmed MEK inhibition enhances presentation of targetable MHC-I tumor antigens in mutant melanomas
title_short MEK inhibition enhances presentation of targetable MHC-I tumor antigens in mutant melanomas
title_sort mek inhibition enhances presentation of targetable mhc-i tumor antigens in mutant melanomas
topic Biological Sciences
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9894220/
https://www.ncbi.nlm.nih.gov/pubmed/36454758
http://dx.doi.org/10.1073/pnas.2208900119
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