The new role for an old guy: MYC as an immunoplayer

Abstract

As an oncogene, myelocytomatosis oncogene (MYC) is implicated in the concept of “oncogene addiction,” where switching off the oncogene leads to the cell cycle arrest and cell differentiation. However, recent data suggest that MYC also controls the establishment of the tumour microenvironment and that “oncogene addiction” actually has a strong immune background. Evaluation of the MYC role in the immunoediting process led to the speculation that cancer just uses and distorts the physiological mechanism by which MYC normally prevents rapidly proliferating cells from the elicitation of an autoimmune response. Concordantly, elevated levels of MYC and induction of immunosuppressive molecules are observed during the processes of growth and development, tissue repair, placenta development, and so forth, implying that MYC may be involved in saving regular physiologically proliferating cells from the immune system attack. Even more, a growing body of evidence suggests MYC involvement in the shaping of the adaptive immune response, immunological memory development, and establishment of immunotolerance. This paper offers an overview of MYC actions in the context of modulation of the immune response in pathological and physiological conditions. The determination of such a new role for a well‐known oncogene opens new perspectives in biomedicine, and consequently, in the treatment of various pathological conditions.

MYC as a target for cancer treatment

“…In addition to these cell intrinsic effects, MYC has also been shown to alter the tumor microenvironment and promote immune evasion [4,17,[55][56][57][58]. Thus in a mutant KRAS mouse model of liver cancer, Xu et al [17] showed that upregulation of MYC resulted in an influx of inflammatory cells such as neutrophils and macrophages into tumors.…”

“…Consistent with MYC being a driver of tumorigenesis, suppression of its expression or inhibition of its function can reverse tumorigenesis [59][60][61][62][63]. This regression of tumorigenesis is mediated by reversal of the carcinogenic processes mentioned above, including, some or all of the following: promotion of cell cycle arrest, triggering of apoptosis, induction of senescence, promotion of differentiation, inhibition of angiogenesis, extrusion of tumor infiltrating inflammatory cells such as macrophages and neutrophils, influx of T and NK cells, reduced levels of PD-L1 and upregulation of an anti-tumor immune response [4,[55][56][57][58]. Indeed, in some situations, even brief or partial suppression of MYC has been shown to reverse tumorigenesis [4,58,59].…”

The Diminishment of Novel Endometrial Carcinoma-Derived Stem-like Cells by Targeting Mitochondrial Bioenergetics and MYC

“…Accordingly, flow cytometric analysis of the isolated 100% CD44-positive ECSC populations revealed over 93% positive PD-L1 and 99% PD-L2 expressing cells, substantiating the link between stemness and immune evasion of ECSCs. Accordingly, the proto-oncogene MYC has been shown to contribute to immunosuppression by directly inducing PD-L1 expression, while the downregulation of MYC led to immune cell infiltration (reviewed in [ 39 ]).…”

Low Expression of IL-15 and NKT in Tumor Microenvironment Predicts Poor Outcome of MYCN-Non-Amplified Neuroblastoma

“…Although MYCN is distinct from MYC (c-myc) [33,34], they are known to share prominent but incomplete redundancy [31]. Recent studies indicate that MYC not only acts as an oncogene but also directly regulates immune responses by various mechanisms that facilitate immune evasion and immunosuppression [35][36][37]. However, whether MYCN in NBL exerts a similar effect on immune regulation as MYC does in other cancers remains to be investigated.…”