The MYC oncogene is a global regulator of the immune response

Abstract

The MYC proto-oncogene is a gene product that coordinates the transcriptional regulation of a multitude of genes that are essential to cellular programs required for normal as well as neoplastic cellular growth and proliferation, including cell cycle, self-renewal, survival, cell growth, metabolism, protein and ribosomal biogenesis, and differentiation. Here, we propose that MYC regulates these programs in a manner that is coordinated with a global influence on the host immune response. MYC had been presumed to contribute to tumorigenesis through tumor cell-intrinsic influences. More recently, MYC expression in tumor cells has been shown to regulate the tumor microenvironment through effects on both innate and adaptive immune effector cells and immune regulatory cytokines. Then, MYC was shown to regulate the expression of the immune checkpoint gene products CD47 and programmed death-ligand 1. Similarly, other oncogenes, which are known to modulate MYC, have been shown to regulate immune checkpoints. Hence, MYC may generally prevent highly proliferative cells from eliciting an immune response. MYC-driven neoplastic cells have coopted this mechanism to bypass immune detection. Thus, MYC inactivation can restore the immune response against a tumor. MYC-induced tumors may be particularly sensitive to immuno-oncology therapeutic interventions.

Functional and Mechanistic Interrogation of BET Bromodomain Degraders for the Treatment of Metastatic Castration-resistant Prostate Cancer

“…This result supports previous studies that have shown BET inhibition to boost antitumor immune responses, and suggests that targeting BET proteins in combination with immune checkpoint inhibitors may potentially elicit a synergistic response (34). Furthermore, c-MYC-driven tumors are reported to have intrinsic tumor cell autonomous regulation and suppression of both innate and adaptive immune responses, and inhibition of MYC restores immune responses to tumor cells (35).…”

Analysis of DNA methylation patterns in the tumor immune microenvironment of metastatic melanoma

“…Our analyses with immune‐poor melanomas stratified by MITF immunostaining suggested transcriptional upregulation of β‐catenin‐dependent canonical Wnt signaling pathway along with the upregulation of c‐Myc in the MITF‐positive group. Immune evasion through upregulation of canonical Wnt signaling pathway is common in melanomas (Spranger et al , 2015), and the role of c‐Myc in the immune exclusion process has previously been described (reviewed in Casey et al , 2018). Since β‐catenin‐induced melanomas require functional MITF (Schepsky et al , 2006; Widlund et al , 2002) and loss of MITF expression affects the corresponding expression of c‐Myc (Seoane et al , 2019), thus the role of MITF seems important in distinction of the immune evasion mechanisms in melanoma.…”

Deep and Prolonged Response to Aurora A Kinase Inhibitor and Subsequently to Nivolumab in MYCL1-Driven Small-Cell Lung Cancer: Case Report and Literature Review

“…Activation of MYC family of genes has been shown to sensitize tumors to Aurora kinase inhibitors [17]. MYC, MYCN, and MYCL are three versions of a family of genes that regulate multiple activities involving cell cycle, growth, metabolism, differentiation, apoptosis, transformation, and immune-regulation [18,19]. Although JAZF1-MYCL1 fusion has never been characterized before, a similar fusion involving RLF-MYCL1 has been well characterized in SCLC samples [20,21].…”

“…These findings strongly suggest MYC as a central regulator of global tumor-immune response. MYC-dependent tumors may be sensitive to immunotherapeutic agents and MYC expression may be a good biomarker for such sensitivity [19]. In addition to these, BET inhibitors appear to target MYC dependence in various malignancies by downregulating transcription of MYC, MYC-dependent target genes, and CD274 (encoding PD-L1) [28,29], and their action was synergistic when used in combination with PD-L1 blockers [30,31].…”