MYC: Master Regulator of Immune Privilege

Abstract

Cancers are often initiated by genetic events that activate proto-oncogenes or inactivate tumor-suppressor genes. These events are also crucial for sustained tumor cell proliferation and survival, a phenomenon described as oncogene addiction. In addition to this cell-intrinsic role, recent evidence indicates that oncogenes also directly regulate immune responses, leading to immunosuppression. Expression of many oncogenes or loss of tumor suppressors induces the expression of immune checkpoints that regulate the immune response, such as PD-L1. We discuss here how oncogenes, and in particular MYC, suppress immune surveillance, and how oncogene-targeted therapies may restore the immune response against tumors.

Figure 1

Proto-oncogene and Oncogene Mediated Regulation of Immune Privilege We suggest a model where in normal physiological situations requiring rapid proliferative expansion, such as during development, tissue regeneration, and immune response (left, top panel) or during pathological conditions such as tumor growth (left, bottom panel), oncogenes such as MYC induce immune checkpoint expression, thereby allowing immunologic privilege. However, oncogene inactivation can elicit immune recognition, which in normal cells can be associated with quiescence (right, top panel) but in tumor cells can be associated with immune response and tumor elimination (right, bottom panel). Further, MYC inactivation in tumors appears to engage the immune system to elicit cellular senescence in tumor cells and to collapse the vascular endothelial cells. MYC-driven tumors necessarily might express high levels of immune checkpoints suppressing immune response and thereby evade immune surveillance, but this oncogene addiction through immune checkpoints may also render them highly susceptible to immunotherapy.