Abstract
MHC-I and MHC-II regulators in lymphomas, some of which had subtype or tumor specificity, were identified.
Major Finding: MHC-I and MHC-II regulators in lymphomas, some of which had subtype or tumor specificity, were identified.
Concept: Inhibitors of the epigenetic enzyme EZH2 and thymidylate synthase increased MHC-I surface expression.
Impact: This work identifies potentially targetable vulnerabilities that could enhance immunotherapies.
To facilitate immune evasion, many cancers downregulate or induce mislocalization of MHC-I, as is seen in 40% to 75% of diffuse large B-cell lymphoma (DLBCL) biopsies. Using genome-wide, CRISPR –Cas9-based screens, Dersh and colleagues identified dozens of genes involved in regulating MHC-I surface expression in activated B cell–like (ABC) and germinal center B cell–like (GCB) DLBCL, including many that had not previously been established as having roles in antigen processing and presentation. Regulators were involved in a variety of cellular functions, including epigenetic regulation, mRNA splicing, protein folding, and trafficking. Interestingly, the screen also revealed that ABC DLBCLs were generally resistant to surface upregulation of MHC-I, whereas GBC DLBCLs did not exhibit this property, and the deletion of some genes even had opposite effects on MHC-I surface expression in different tumor lines. Some genes coregulated MHC-I and MHC-II surface expression, including the positive regulator SUGT1, a little-studied gene whose homolog in plants encodes an HSP90 co-chaperone. An additional screen was conducted in search of small-molecule drug candidates that increase MHC-I surface selection, with the drug candidates selected because they inhibited negative regulators in the genetic screen or because they have established immunomodulatory properties. This screen revealed that inhibitor of EZH2 (the catalytic subunit of the epigenetic enzyme PRC2) and thymidylate synthase (which catalyzes a rate-limiting step in DNA synthesis) enhanced MHC-I antigen presentation and thus may be of use in supplementing immunotherapies for DLBCL. In summary, this work provides detailed information pinpointing regulators of MHC-I surface expression in DLBCL, suggesting potential drug targets to enhance current treatments.
Note: Research Watch is written by Cancer Discovery editorial staff. Readers are encouraged to consult the original articles for full details. For more Research Watch, visit Cancer Discovery online at http://cancerdiscovery.aacrjournals.org/CDNews.
