Skip to main content
bioRxiv
  • Home
  • About
  • Submit
  • ALERTS / RSS
Advanced Search
New Results

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

View ORCID ProfileLauren E. Stopfer, View ORCID ProfileNicholas J. Rettko, View ORCID ProfileOwen Leddy, View ORCID ProfileJoshua M. Mesfin, Eric Brown, View ORCID ProfileShannon Winski, View ORCID ProfileBryan Bryson, James A. Wells, View ORCID ProfileForest M. White
doi: https://doi.org/10.1101/2022.01.10.475285
Lauren E. Stopfer
1Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge, MA 02139, USA
2Koch Institute for Integrative Cancer Research, Center for Precision Cancer Medicine, Massachusetts Institute of Technology, Cambridge, MA 02139, USA
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
  • ORCID record for Lauren E. Stopfer
Nicholas J. Rettko
3Department of Pharmaceutical Chemistry, University of California San Francisco, San Francisco, CA, 94158, USA
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
  • ORCID record for Nicholas J. Rettko
Owen Leddy
1Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge, MA 02139, USA
2Koch Institute for Integrative Cancer Research, Center for Precision Cancer Medicine, Massachusetts Institute of Technology, Cambridge, MA 02139, USA
4Ragon Institute of MGH, MIT, and Harvard, Cambridge, Massachusetts, 02139, USA
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
  • ORCID record for Owen Leddy
Joshua M. Mesfin
1Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge, MA 02139, USA
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
  • ORCID record for Joshua M. Mesfin
Eric Brown
5Pfizer Boulder Research & Development, Boulder, CO 8030, USA
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Shannon Winski
5Pfizer Boulder Research & Development, Boulder, CO 8030, USA
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
  • ORCID record for Shannon Winski
Bryan Bryson
1Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge, MA 02139, USA
4Ragon Institute of MGH, MIT, and Harvard, Cambridge, Massachusetts, 02139, USA
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
  • ORCID record for Bryan Bryson
James A. Wells
3Department of Pharmaceutical Chemistry, University of California San Francisco, San Francisco, CA, 94158, USA
6Chan Zuckerberg Biohub, San Francisco, CA, 94158, USA
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Forest M. White
1Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge, MA 02139, USA
2Koch Institute for Integrative Cancer Research, Center for Precision Cancer Medicine, Massachusetts Institute of Technology, Cambridge, MA 02139, USA
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
  • ORCID record for Forest M. White
  • For correspondence: fwhite@mit.edu
  • Abstract
  • Full Text
  • Info/History
  • Metrics
  • Supplementary material
  • Preview PDF
Loading

SUMMARY

Combining multiple therapeutic strategies in NRAS/BRAF mutant melanoma – namely MEK/BRAF kinase inhibitors, immune checkpoint inhibitors, 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 alters anti-tumor immunity by utilizing quantitative immunopeptidomics to profile changes the peptide MHC (pMHC) repertoire. These data reveal a collection of tumor antigens whose presentation levels are selectively augmented following therapy, including several epitopes present at over 1000 copies-per-cell. We leveraged the tunable abundance of MEKi-modulated antigens by targeting 4 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.

Competing Interest Statement

The authors have declared no competing interest.

Copyright 
The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. All rights reserved. No reuse allowed without permission.
Back to top
PreviousNext
Posted January 12, 2022.
Download PDF

Supplementary Material

Email

Thank you for your interest in spreading the word about bioRxiv.

NOTE: Your email address is requested solely to identify you as the sender of this article.

Enter multiple addresses on separate lines or separate them with commas.
MEK inhibition enhances presentation of targetable MHC-I tumor antigens in mutant melanomas
(Your Name) has forwarded a page to you from bioRxiv
(Your Name) thought you would like to see this page from the bioRxiv website.
CAPTCHA
This question is for testing whether or not you are a human visitor and to prevent automated spam submissions.
Share
MEK inhibition enhances presentation of targetable MHC-I tumor antigens in mutant melanomas
Lauren E. Stopfer, Nicholas J. Rettko, Owen Leddy, Joshua M. Mesfin, Eric Brown, Shannon Winski, Bryan Bryson, James A. Wells, Forest M. White
bioRxiv 2022.01.10.475285; doi: https://doi.org/10.1101/2022.01.10.475285
Digg logo Reddit logo Twitter logo Facebook logo Google logo LinkedIn logo Mendeley logo
Citation Tools
MEK inhibition enhances presentation of targetable MHC-I tumor antigens in mutant melanomas
Lauren E. Stopfer, Nicholas J. Rettko, Owen Leddy, Joshua M. Mesfin, Eric Brown, Shannon Winski, Bryan Bryson, James A. Wells, Forest M. White
bioRxiv 2022.01.10.475285; doi: https://doi.org/10.1101/2022.01.10.475285

Citation Manager Formats

  • BibTeX
  • Bookends
  • EasyBib
  • EndNote (tagged)
  • EndNote 8 (xml)
  • Medlars
  • Mendeley
  • Papers
  • RefWorks Tagged
  • Ref Manager
  • RIS
  • Zotero
  • Tweet Widget
  • Facebook Like
  • Google Plus One

Subject Area

  • Cancer Biology
Subject Areas
All Articles
  • Animal Behavior and Cognition (3502)
  • Biochemistry (7343)
  • Bioengineering (5319)
  • Bioinformatics (20258)
  • Biophysics (10008)
  • Cancer Biology (7735)
  • Cell Biology (11293)
  • Clinical Trials (138)
  • Developmental Biology (6434)
  • Ecology (9947)
  • Epidemiology (2065)
  • Evolutionary Biology (13315)
  • Genetics (9359)
  • Genomics (12579)
  • Immunology (7696)
  • Microbiology (19008)
  • Molecular Biology (7437)
  • Neuroscience (41011)
  • Paleontology (300)
  • Pathology (1228)
  • Pharmacology and Toxicology (2134)
  • Physiology (3155)
  • Plant Biology (6858)
  • Scientific Communication and Education (1272)
  • Synthetic Biology (1895)
  • Systems Biology (5311)
  • Zoology (1087)