Cancer Survival Strategies: Evading the Immune System

SCENARIO 5 Abnormal cell growth SCENARIO Normal cells can change their characteristics and develop into benign and malignant neoplasms due to various factors. The body's immune system will respond and inhibit the development of abnormal cells. The ability of cells to evade the immune system, initiate an inflammatory response, avoid cell death, and increase proliferation signals causes malignant neoplasm cells to continue to grow. Explain the nature and survival mechanisms of cancer cells/malignant neoplasms (four principles. Avoids the immune system Still unresolved issues surrounding tumor formation involve the role the immune system plays in fighting or eradicating the formation and progression of incipient neoplasia, late-stage tumors, and micrometastases. The old theory of immune surveillance proposes that cells and tissues are constantly monitored by an evervigilant immune system, and that this immune surveillance is responsible for recognizing and eliminating most incipient cancer cells as well as newly formed tumors. According to logic, the emerging solid tumors have somehow managed to evade detection by various arms of the immune system or have been able to limit the rate of immunological killing, thereby avoiding destruction. The role of immunological monitoring of impaired tumors appears to be validated by the marked increase in certain cancers in immunocompromised individuals. However, the vast majority are cancers caused by viruses, indicating that most control of this class of cancer usually relies on reducing the viral load in infected individuals, in part through elimination of virus-infected cells. These observations seem to shed some light on the possible role of the immune system in limiting formation> 80% of tumors of nonviral etiology. However, in recent years, increasing evidence, both from genetically engineered mice and from clinical epidemiology, suggests that the immune system acts as a significant barrier to tumor formation and progression, at least in some forms of cancer that are not caused by viruses. When mice genetically engineered to lack various components of the immune system were assessed for the development of carcinogen-induced tumors, it was observed that tumors appeared more frequently and/or grew more rapidly in immunodeficient mice relative to immunocompetent controls. Specifically, deficiencies in the development or function of CD8+ cytotoxic T lymphocytes (CTL), CD4+ Th1 helper T cells, or natural killer (NK) cells each lead to a demonstrable increase in tumor incidence; in addition, mice with combined immunodeficiency in T cells and NK cells were even more susceptible to cancer development. The results suggest that, at least in certain experimental models, both the innate and adaptive cellular arms of the immune system can contribute significantly to immune surveillance and thereby tumor eradication. Additionally, transplantation experiments have shown that cancer cells that initially arise in immunocompetent mice are often inefficient at initiating secondary tumors in immunocompetent hosts, whereas cancer cells from tumors that arise in immunocompetent mice are equally efficient at initiating tumor transplantation in both tumor types. This behavior has been interpreted as follows: Highly immunogenic clones of cancer cells are routinely eliminated in immunocompetent hosts—a process referred to as ‘‘immunoediting’’—leaving only weakly immunogenic variants to grow and produce solid tumors; These weak immunogenic cells can then colonize immunodeficient and immunocompetent hosts. In contrast, when arising in immunodeficient hosts, immunogenic cancer cells are not selectively depleted and instead, may co-evolve with their immunogenic counterparts. When cells from unedited tumors are serially transplanted into recipientssyngeneic, Immunogenic cancer cells are rejected when they encounter for the first time the competent immune system of their secondary host. Clinical epidemiology also increasingly supports the existence of an antitumor immune response in several forms of human cancer. For example, patients with colon and ovarian tumors that are abundantly infiltrated with CTL and NK cells have a better prognosis than those lacking abundant killer lymphocytes; cases for other cancers are suggestive but less compelling and are the subject of ongoing investigation. Additionally, some immunosuppressed organ transplant recipients have been observed to develop donor-derived cancers, suggesting that in ostensibly tumor-free donors, cancer cells are held in check, in a dormant state, by a fully functioning immune system. However, the epidemiology of patients with chronic immunosuppression does not show a significant increase in the incidence of major forms of nonviral human cancer, as noted above. This may be considered an argument against the importance of immune surveillance as an effective barrier to tumorigenesis and tumor progression. It has been suggested that HIV and pharmacologically immunosuppressed patients are largely immunodeficient in the T and B cell compartments and thus do not exhibit the multicomponent immunologic deficiencies that have been produced in genetically engineered mutant mice lacking NK cells and CTLs; this opens the possibility that these patients still have residual capacity for immunological defense against cancer mounted by NK and other innate immune cells. In fact, the above discussion of cancer immunology simplifies tumorhost immunology interactions, as highly immunogenic cancer cells may evade immune destruction by deactivating components of the immune system that have been sent to eliminate them. For example, cancer cells can paralyze CTL and NK cell infiltration, by secreting TGF-b or other immunosuppressive factors. A more subtle mechanism operates through the recruitment of actively immunosuppressive inflammatory cells, including regulatory T cells (Tregs) and myeloid-derived suppressor cells (MDSCs). Both can suppress the action of cytotoxic lymphocytes.