MYC Overexpression Drives Immune Evasion in Human Cancer that is Reversible Through Restoration of Pro-Inflammatory Macrophages

Abstract

Cancers evade immune surveillance that in some, but not in many, cases can be reversed through immune checkpoint therapy. Here we report that the MYC oncogene suppresses immune surveillance, activates immune checkpoint expression, and predicts responsiveness to immune checkpoint inhibition. First, when MYC is genomically amplified and overexpressed in 33 different human cancers, this increases immune checkpoint expression, drives immune checkpoint therapeutic resistance, and is associated with both Th2-like immune profile, and reduced CD8 T cell infiltration. Second, experimentally, MYC-driven tumors suppress pro-inflammatory antigen-presenting macrophages with increased CD40 and MHCII expression, which in turn impedes T cell response. This MYC-driven suppression of macrophages can be reversed by combined but not individual blockade of PDL1 and CTLA4. Third, the depletion of macrophages abrogated the anti-neoplastic effects of PDL1 and CTLA4 blockade. Hence, MYC is a predictor of immune checkpoint responsiveness and a key driver of immune evasion through the suppression of pro-inflammatory macrophages. The immune evasion by MYC can be overcome by combined PDL1 and CTLA4 blockade.Statement of SignificanceMYC is the most commonly activated oncogene in human cancers. In this study, we identify macrophage-mediated immune evasion as a major therapeutic vulnerability of MYC-driven cancers. Our results have implications for developing effective immunotherapies for MYC-driven human cancers and also for prioritizing patients with MYC-driven tumors for combination immunotherapy.

Association with TFIIIC limits MYCN localization in hubs of active promoters and chromatin accumulation of non-phosphorylated RNA Polymerase II

“…Both MYC and MYCN bind to virtually all active promotors and profoundly alter the dynamics of RNA polymerase II (RNAPII) transcription, with an increase in pause release and elongation being most apparent (Herold, Kalb et al, 2019, Walz, Lorenzin et al, 2014. One consequence of these changes are alterations in expression of a broad range of target genes (Dhanasekaran, Hansen et al, 2023). Unrelated to those changes in gene expression, MYC and MYCN also control RNAPII function to limit the accumulation of R-loops, to facilitate promoter-proximal double-strand break repair and to co-ordinate transcription elongation with DNA replication (Papadopoulos, Uhl et al, 2023).…”