The MYC oncogene - the grand orchestrator of cancer growth and immune evasion

Abstract

The MYC proto-oncogenes encode a family of transcription factors that are among the most commonly activated oncoproteins in human neoplasias. Indeed, MYC aberrations or upregulation of MYC-related pathways by alternate mechanisms occur in the vast majority of cancers. MYC proteins are master regulators of cellular programmes. Thus, cancers with MYC activation elicit many of the hallmarks of cancer required for autonomous neoplastic growth. In preclinical models, MYC inactivation can result in sustained tumour regression, a phenomenon that has been attributed to oncogene addiction. Many therapeutic agents that directly target MYC are under development; however, to date, their clinical efficacy remains to be demonstrated. In the past few years, studies have demonstrated that MYC signalling can enable tumour cells to dysregulate their microenvironment and evade the host immune response. Herein, we discuss how MYC pathways not only dictate cancer cell pathophysiology but also suppress the host immune response against that cancer. We also propose that therapies targeting the MYC pathway will be key to reversing cancerous growth and restoring antitumour immune responses in patients with MYC-driven cancers.

Fig. 1 |. Major genetic alterations involving MYC and its paralogues in human cancers.

Prevalence of gene amplification of the three MYC paralogues MYC, MYCL and MYCN across 16 major human cancer types in The Cancer Genome Atlas.

Fig. 2 |. Mechanisms leading to MYC activation in human cancers.

a | Genetic aberrations, such as chromosomal translocations and genomic amplifications, lead to increased MYC mRNA expression. b | Alteration of upstream regulatory pathways can lead to increased or decreased transcription of the MYC oncogene. c | Post-translational modifications of the MYC protein, such as preferential phosphorylation of the serine 62 (S62) residue versus threonine 58 (T58), can block degradation and promote stabilization of MYC, thereby enhancing activation of the MYC pathway.

Fig. 3 |. MYC is a grand orchestrator of the hallmarks of cancer.

MYC regulates several cancer cell-intrinsic and host-dependent pathways to promote cancer cell growth and survival (green area). Cancer cell-intrinsic processes regulated by MYC include proliferation, metabolism, invasiveness, autophagy, and protein and ribosomal biosynthesis. MYC also simultaneously blocks other cellular protective mechanisms, such as differentiation or senescence, thereby promoting cancer progression (red area). Paradoxically, MYC also induces cellular processes, such as apoptosis and chromosomal instability, that can be detrimental to cancer cell survival (orange arrows). The delicate balance between these events and cellular context ultimately determines cell fate. Furthermore, MYC controls the ability of cancer cells to undergo dormancy and to overcome nutrient-low environments, eventually leading to tumour relapse. To maintain this quiescent state, MYC inhibits several cellular programmes, including cell differentiation and senescence. MYC activation in the cancer cells also drives enhanced angiogenesis, thus promoting tumour progression. Finally, one of the most important functions of MYC is to enable cancer cells to evade and inhibit immune surveillance to safeguard their survival. All of these hallmarks regulated by MYC work in unison to drive cancer progression.

Fig. 4 |. MYC blocks immune surveillance.

MYC enables cancers to evade the immune system through several distinct mechanisms. a | MYC regulates the expression and production of several immune ligands or receptors and immune effector molecules, such as PD-L1, CD47, MHC classes I and II, and NKG2D. MYC also promotes the expression of several cytokines, such as CCL2, IL-23 and CCL9, which regulate the conversion of antitumour M1 macrophages to pro-tumour M2 macrophages and prevent the activation and recruitment of B cells, natural killer (NK) cells, and CD4⁺ and CD8⁺ T cells. CCL9 activates mast cells, which in turn induce angiogenesis. b | Upon inactivation of MYC, the downregulation of PD-L1 and CD47 results in the rapid recruitment and activation of CD8⁺ T cells and NK cells. The inactivation of MYC also increases the levels of NKG2DL in cancer cells, resulting in NK cell recruitment. The production of most of the cytokines described above decreases upon MYC inactivation. By contrast, the expression of type I interferons and CCL5 increases upon MYC inactivation, resulting in the recruitment and activation of NK cells and B cells and of CD8⁺ T cells, respectively. Thus, MYC controls the immune status of a tumour by creating an immunosuppressive ‘cold’ tumour microenvironment when activated, which reverts to an immune-sensitive ‘hot’ milieu when inactivated. TSP1, thrombospondin 1.

Fig. 5 |. Therapeutic strategies to target MYC-driven tumours.

Among the multiple strategies currently explored to target MYC-driven tumours, the majority use indirect approaches (grey boxes) such as those based on inhibiting MYC synthetic lethal genes or interfering with the expression of MYC at the DNA, RNA or protein level. Direct strategies to inhibit MYC (blue box) include approaches using small molecules, peptides or ‘miniproteins’ to inhibit MYC–MAX dimerization, sequester MAX via homodimer stabilization, or interfering with MYC–MAX binding to target DNA sequences. Ac, acetylation; CDKs, cyclin-dependent kinases; HDACs, histone deacetylases; Me, methylation; P, phosphorylation; Ub, ubiquitylation.

Fig. 6 |. Proposed biomarker-stratified therapeutic strategies to target MYC-driven cancers.

Patients with cancer can be assigned to MYC^hi and MYC^low subgroups defined by enrichment of an MYC activation signature in tumour samples. Patients with MYC-driven tumours can potentially be further classified according to various disease phenotypes on the basis of the dominant mechanism of action of MYC, which would enable stratification to receive different treatments. For example, patients harbouring tumours with MYC amplifications could be treated with direct MYC inhibitors, whereas those with enrichment of synthetic lethal targets of MYC would receive agents targeting these specific gene products. By contrast, MYC-directed therapies could be used to sensitize MYC^hi immunologically ‘cold’ tumours to immunotherapies, whereas patients with tumours in which MYC prominently induces metabolic dysregulation can be treated with drugs targeting these pathways. In summary, discoveries elucidating the specific mechanisms by which MYC drives cancer are enabling the development of novel and selective therapeutic strategies to target MYC in human cancers.