Can Antitumor Immunity Help to Explain “Oncogene Addiction”?

Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA.
Cancer cell (Impact Factor: 23.52). 11/2010; 18(5):403-5. DOI: 10.1016/j.ccr.2010.11.002
Source: PubMed


"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.

8 Reads
  • Source
    • "Second, oncogene inactivation could activate an immune response through immunogenic cell death that in turns activates the immune response [80]. Identifying the specific mechanism of the immune activation and response could suggest important strategies for monitoring and implementing a therapeutic response [10]. "
    [Show abstract] [Hide abstract]
    ABSTRACT: The targeted inactivation of a single oncogene can induce dramatic tumor regression, suggesting that cancers are "oncogene addicted." Tumor regression following oncogene inactivation has been thought to be a consequence of restoration of normal physiological programs that induce proliferative arrest, apoptosis, differentiation, and cellular senescence. However, recent observations illustrate that oncogene addiction is highly dependent upon the host immune cells. In particular, CD4(+) helper T cells were shown to be essential to the mechanism by which MYC or BCR-ABL inactivation elicits "oncogene withdrawal." Hence, immune mediators contribute in multiple ways to the pathogenesis, prevention, and treatment of cancer, including mechanisms of tumor initiation, progression, and surveillance, but also oncogene inactivation-mediated tumor regression. Data from both the bench and the bedside illustrates that the inactivation of a driver oncogene can induce activation of the immune system that appears to be essential for sustained tumor regression.
    07/2014; 2(1):24. DOI:10.1186/2051-1426-2-24
  • Source
    • "While a wide variety of stromal elements contribute to the formation of this specialized environment, tumor cells [99, 118] and tumor-associated macrophages [67, 68, 74, 100, 117] secrete many of the key inflammatory mediators, including the growth factors, cytokines, chemokines, prostaglandins, and metaloproteases described above. Elaboration of these crucial factors may be driven by transcriptional activation caused by oncogenic mutations [119], toll-like receptor (TLR) signal transduction [99, 118], and/or cytokine- or growth factor-mediated signaling [74, 99]. Particularly important to the immune tolerogenic properties of the tumor are the effects of TGF-β secretion [59], including suppression of T-cell adaptive and natural killer (NK) cell innate antitumor responses, recruitment of suppressive myeloid cell subsets such as suppressive dendritic cells, TAMs, and MDSCs, and recruitment of regulatory T cell activity [7, 12, 59, 73]. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Central nervous system tumors take advantage of the unique immunology of the CNS and develop exquisitely complex stromal networks that promote growth despite the presence of antigen-presenting cells and tumor-infiltrating lymphocytes. It is precisely this immunological paradox that is essential to the survival of the tumor. We review the evidence for functional CNS immune privilege and the impact it has on tumor tolerance. In this paper, we place an emphasis on the role of tumor-infiltrating myeloid cells in maintaining stromal and vascular quiescence, and we underscore the importance of indoleamine 2,3-dioxygenase activity as a myeloid-driven tumor tolerance mechanism. Much remains to be discovered regarding the tolerogenic mechanisms by which CNS tumors avoid immune clearance. Thus, it is an open question whether tumor tolerance in the brain is fundamentally different from that of peripheral sites of tumorigenesis or whether it simply stands as a particularly strong example of such tolerance.
    Clinical and Developmental Immunology 01/2012; 2012(5-6):937253. DOI:10.1155/2012/937253 · 2.93 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: OTHER THEMES PUBLISHED IN THIS IMMUNOLOGY IN THE CLINIC REVIEW SERIES Metabolic Diseases, Host Responses, Allergies, Autoinflammatory Diseases, Type 1 diabetes and viruses. 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.
    Clinical & Experimental Immunology 02/2012; 167(2):188-94. DOI:10.1111/j.1365-2249.2011.04514.x · 3.04 Impact Factor
Show more