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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

Nevada RNformation, 2022-12, Vol.119 (49), p.e2208900119 [Periódico revisado por pares]

United States: Nevada Nurses Association

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Título:
MEK inhibition enhances presentation of targetable MHC-I tumor antigens in mutant melanomas
Autor: Stopfer, Lauren E ; Rettko, Nicholas J ; Leddy, Owen ; Mesfin, Joshua M ; Brown, Eric ; Winski, Shannon ; Bryson, Bryan ; Wells, James A ; White, Forest M
Assuntos: Antibodies ; Antigen (tumor-associated) ; Antigen presentation ; Antigenic determinants ; Antigens ; Antigens, Neoplasm - genetics ; Biological products ; Biological Sciences ; Epitopes ; Health aspects ; Humans ; Immune checkpoint inhibitors ; Immunotherapy ; Inhibitors ; Kinases ; Lymphocytes ; Lymphocytes T ; Major histocompatibility complex ; Melanoma ; Melanoma - drug therapy ; Melanoma - genetics ; Mitogen-Activated Protein Kinase Kinases - genetics ; Mutants ; Peptides ; Proto-Oncogene Proteins B-raf - genetics ; T cells ; Tumor antigens ; Tumor cells ; Tumors
É parte de: Nevada RNformation, 2022-12, Vol.119 (49), p.e2208900119
Notas: 1L.E.S. and N.J.R. contributed equally to this work.
Edited by Philippa Marrack, National Jewish Health, Denver, CO; received May 23, 2022; accepted October 28, 2022
Descrição: 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.
Editor: United States: Nevada Nurses Association
Idioma: Inglês

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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

United States: Nevada Nurses Association

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