Immunology in the clinic review series; focus on cancer: multiple roles for the immune system in oncogene addiction

Abstract

Despite complex genomic and epigenetic abnormalities, many cancers are irrevocably dependent on an initiating oncogenic lesion whose restoration to a normal physiological activation can elicit a dramatic and sudden reversal of their neoplastic properties. This phenomenon of the reversal of tumorigenesis has been described as oncogene addiction. Oncogene addiction had been thought to occur largely through tumour cell-autonomous mechanisms such as proliferative arrest, apoptosis, differentiation and cellular senescence. However, the immune system plays an integral role in almost every aspect of tumorigenesis, including tumour initiation, prevention and progression as well as the response to therapeutics. Here we highlight more recent evidence suggesting that oncogene addiction may be integrally dependent upon host immune-mediated mechanisms, including specific immune effectors and cytokines that regulate tumour cell senescence and tumour-associated angiogenesis. Hence, the host immune system is essential to oncogene addiction.

Fig. 1

Oncogene addiction comprises both cell-autonomous and non-cell-autonomous mechanisms of tumour regression. (a) Oncogene activation leads to tumorigesis through suppression of critical safeguards and engagement of hallmarks of tumour growth. (b) Oncogene inactivation reverses the hallmarks of cancer to lead to tumour regression through reinstatement of cell-intrinsic programmes such as apoptosis, proliferative arrest, differentiation and senescence, as well as cell-extrinsic phenomena such as host immunity and suppression of angiogenesis.

Fig. 2

The immune system is critical to oncogene addiction. Immediately upon oncogene inactivation, tumour regression occurs regardless of host immune status as a result of proliferative arrest, apoptosis and/or differentiation. However, the absence of the host immune system leads inevitably to tumour relapse. In the presence of host immuneity, particularly CD4⁺ T cells, oncogene inactivation induces cellular senescence and suppresses angiogenesis, leading to sustained tumour regression.