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Methods for Modulating MHC-I Expression in Merkel Cell Carcinoma

Genome-scale CRISPR-CaS9 knockout and open reading frame gain-of-function screens identified genes that impact MHC expression

  • Therapeutics

Project Overview

  • Merkel cell carcinoma (MCC) is a very rare, but highly aggressive neuroendocrine skin cancer that is attributed to the Merkel cell polyomavirus in 80% of cases.
  • Many cancers present with decreased expression of major histocompatibility complex class I (MHC-I), leading to cancer cell evasion of immune system recognition through a common target known as human leukocyte antigen class 1 (HLA 1). HLA 1 expression is reduced in MCC, as well as many other cancers. Therefore, increasing levels of MHC-1 molecules, such as HLA 1, may serve as a mechanism of improving immune system detection of tumors. 
  • Dana-Farber scientists have developed a small molecule to increase MHC-1 levels in tumors.
  • Dana-Farber is seeking an exclusive license for this technology.

Technology

Genome-scale CRISPR-CaS9 knockout and open reading frame (ORF) gain-of-function screens identified genes that impact MHC expression in MCC cell lines derived from tumor biopsies and patient derived xenografts.

Various components of the Polycomb complex, which is often overexpressed in cancer, were discovered to be involved in MHC-I expression. Specifically, three components of the Polycomb repressive complex 1 (PRC1.1 complex), including Polycomb Group RING Finger Protein 1 (PCGF1), BCL6 Corepressor Like 1 (BCORL1), and Ubiquitin-Specific Protease 7 (USP7), contribute to the repression of MHC-I molecules. Furthermore, knockout of these three components resulted in an increase in MHC-I expression. Small molecule inhibitors of USP7, in particular, increased MHC-I levels in tumor cells.

This invention serves as a potential new method for treating cancer by altering the expression of MHC-I in cancer cells. 

Further Details: 

Reversal of Viral an Epigenetic HLA Class I Repression in Merkel Cell Carcinoma, Keskin and Lee et al. J. Clin. Invest. 2022, 132(12), e151666: DOI: 10.1172/JCI151666 

Team Members: Catherine J. Wu, MD, Sara Buhrlage, PhD, Derin B. Keskin, PhD, James A. DeCaprio, MD

Applications

Clinical use of USP7 inhibitors to upregulate tumor HLA I expression as part of immunotherapy treatment. 

Opportunities

Dana-Farber is seeking an Exclusive License for this technology

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Team Members

Sara Buhrlage, PhD

Principal Investigator, Cancer Biology, Dana-Farber

Associate Professor, Biological Chemistry and Molecular Pharmacology, Harvard Medical School