Immune responses to malignancies

Abstract

Immune responses to tumor-associated antigens (TAs) are often detectable in tumor-bearing hosts, but they fail to eliminate malignant cells or prevent the development of metastases. Patients with cancer generate robust immune responses to infectious agents (bacteria and viruses) perceived as a "danger signal" but only ineffective weak responses to TAs, which are considered as "self." This fundamental difference in responses to self versus nonself is further magnified by the ability of tumors to subvert the host immune system. Tumors induce dysfunction and apoptosis in CD8 + antitumor effector cells and promote expansion of regulatory T cells, myeloid-derived suppressor cells, or both, which downregulate antitumor immunity, allowing tumors to escape from the host immune system. The tumor escape is mediated by several distinct molecular mechanisms. Recent insights into these mechanisms encourage expectations that a more effective control of tumorinduced immune dysfunction will be developed in the near future. Novel strategies for immunotherapy of cancer are aimed at the protection and survival of antitumor effector cells and also of central memory T cells in the tumor microenvironment. KeywordsCancer; immunity; tumor escape; immune suppression; effector T cells Evidence accumulated over the last few years convincingly shows that the host immune system is involved in cancer development and progression, as well as control of metastasis. The presence of antitumor cellular responses, humoral responses, or both to tumorassociated antigens (TAs) has been observed in many, but not all, patients with cancer. 1,2 The evidence for such pre-existing antitumor immunity in patients with cancer confirms that the tumor-bearing host is capable of mounting an immune response to TAs. Tumor progression from a single transformed cell to a mass of malignant cells is a multistep process involving a series of genetic changes occurring in human subjects over a period of months or years and culminating in the established tumor. 3 During this period, neither the host immune system nor the developing tumor are idle: those newly emerging tumor cells that are recognized by the immune system are eliminated only to be replaced by genetic tumor variants resistant to immune intervention and giving rise to a heterogenous population of malignant cells found in any tumor. Tumors are genetically unstable, and the emergence of new genetic variants, which is responsible for the tumor heterogeneity, ensures that the tumor survives in the face of the host immune system. Only the tumor cells that manage to avoid recognition escape and survive, whereas those that are recognized by the immune system are eliminated as soon as they arise. The tumor development involves a prolonged NIH-PA Author ManuscriptNIH-PA Author Manuscript NIH-PA Author Manuscript series of checks and balances between the host attempting to curtail tumor growth and the tumor benefiting from genetic changes, altering its microenvironment and avoiding immune elimination. Thus the...