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 tumor-induced 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.

FIG 1

Effects of the tumor on immune cells. In the tumor microenvironment an excess of immunoinhibitory factors favors the generation and expansion of T_H2-type T cells and Treg cells ather than CTLs and T_H1-type effector cells. The downregulation of MHC molecules and defects in the APM components in DCs, as well as the immunosuppressive effects of accumulating MDSCs on DC maturation and function, contributes to the polarization of immune responses toward tolerance and away from immunity. The balance between stimulatory and suppressive responses shifts in favor of suppression as the tumor grows. Immune therapies are expected to shift this balance back to T_H1-type responses, which promote expansion of CD4⁺ T_H1 cells producing IFN-γ and IL-2, as well as CD8⁺ CTLs. IDO, Indoleamine 2,3-deoxygenase.