Can antitumor immunity help to explain "oncogene addiction"?

Abstract

“Oncogene addiction” refers to the process of tumor cell death that can occur after inactivation of a single oncogene. In this issue of Cancer Cell, Rakhra, et al. argue that complete tumor clearance after molecular targeted therapies requires a functioning immune system, pointing the way toward radically new combination therapies.

Figure 1

Theories of oncogene addiction. A. In the “cumulative mutations” model, tumors accrue mutated oncogenes, some of which are “driver” and some of which are “passenger.” Any change must be neutral or beneficial to the tumor cell’s viability. However, some mutations could occur that are beneficial only in the context of existing mutations but are otherwise harmful. Withdrawal of an early oncogene signal in this scenario would induce senescence or death, like a molecular “house of cards.” B. In the “dominant oncogene” model, tumors receive signals from multiple growth factor pathways but become dependent on one of these. With time, other cell growth pathways become less subject to selection and suffer mutations or epigenetic changes that attenuate or obliterate their functions. Removal of the dominant growth factor signal then triggers apoptosis. Note that arrows represent intracellular signaling pathways. C. The “oncogene amnesia” model, and intact oncogene signal (shown at left) limits cell death. Thus, pathways that would normally induce senescence and death are held in check by the activities of the oncogene, but are re-instated upon withdrawal of the oncogene’s activity (shown at right). D. How mechanisms of immune activation might explain oncogene addiction. When cells experience apoptosis associated with inactivation of an oncogene they might release tumor-associated antigens, which come in the form of tissue differentiation antigens, cancer/testis antigens, or products of mutated genes expressed by the transformed cells. Additional immune activating signals including calreticulin, the S100 family of proteins, and (in secondary necrosis) the high mobility group box 1 protein (HMGB1) can be emitted by some dying cells. Resulting activation of host antigen presenting cells (APC) could in turn activate CD4⁺ T cells capable of producing a host of immunoregulatory and anti-angiogenesis molecules including thrombospondin-1 (TSP1). CD4⁺ T cells recognizing processed tumor-associated antigens also can activate CD8⁺ T cells and natural killer (NK) cells leading to more tumor killing. The activities of immune cells can be inhibited by myeloid-derived suppressor cells (MDSC) and by regulatory T cells (Tregs). However, the administration of tumor-reactive T cells in combination with ablation of regulatory cells can result in long-term durable tumor regression in mice and humans.