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.

Figure 1.

MYC inactivation elicits tumor regression through both tumor-intrinsic and host-dependent mechanisms. Left to right: through tumor-intrinsic mechanisms, inactivation of MYC induces proliferative arrest and apoptosis (left panel). The death of tumor cells through apoptosis may contribute to the immune response by recruiting innate immune cells. Inactivation of MYC suppresses immune checkpoints and recruits an adaptive immune-dependent response (center panel), activating macrophages and CD4⁺ T cells. The final phase of tumor elimination likely involves the recruitment of an immune response through T cells as well as the production of other cytokines. Immune activation has been associated with the remodeling of the tumor microenvironment, including the induction of cellular senescence and the shutdown of angiogenesis. This occurs in part through TSP-1 (right panel).

Figure 2.

MYC can regulate PD-L1 and CD47 immune checkpoint expression. MYC regulates PD-L1 and CD47 mRNA and protein expression in tumor cells. Many other oncogene signaling pathways have been shown to regulate PD-L1, which may also occur through MYC. BRD4, BRAF, EGFR, PI3K/AKT/mTOR, and β-catenin also have been shown to influence PD-L1 expression, and all these gene products are known to regulate MYC mRNA, protein expression, and/or protein stability.