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

被引：18

作者：

Stopfer, Lauren E. ^{[1
,2
]}

Rettko, Nicholas J. ^{[3
]}

Leddy, Owen ^{[1
,2
,4
]}

Mesfin, Joshua M. ^{[1
]}

Brown, Eric ^{[5
]}

Winski, Shannon ^{[5
]}

Bryson, Bryan ^{[1
,4
]}

Wells, James A. ^{[3
,6
]}

White, Forest M. ^{[1
,2
]}

机构：

[1] MIT, Dept Biol Engn, Cambridge, MA 02139 USA

[2] MIT, Koch Inst Integrat Canc Res, Ctr Precis Canc Med, Cambridge, MA 02139 USA

[3] Univ Calif San Francisco, Dept Pharmaceut Chem, San Francisco, CA 94158 USA

[4] Ragon Inst Massachusetts Gen Hosp Massachusetts I, Cambridge, MA 02139 USA

[5] Pfizer Boulder Res & Amp Dev, Boulder, CO USA

[6] Chan Zuckerberg Biohub, San Francisco, CA 94158 USA

来源：

PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA | 2022年 / 119卷 / 49期

关键词：

MHC; immunopeptidomics; antigen presentation; melanoma; ligandomics; T-CELL RECOGNITION; CANCER REGRESSION; BRAF; EXPRESSION; GENE; TRAMETINIB; THERAPY; SPECIFICITY; DABRAFENIB; SURVIVAL;

D O I：

10.1073/pnas.2208900119

中图分类号：

O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];

学科分类号：

07 ; 0710 ; 09 ;

摘要：

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.

引用

页数：11

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