Cancer Immunology
Summary of Key Points
• Cancer is characterized by genetic and epigenetic instability leading to multiple unique and sometimes common mutations and “ectopic” overexpression of many genes normally not expressed in the tissue of origin. These alterations provide antigens that the adaptive immune system can recognize to distinguish the cancer cell from normal cells. Thus the immune system of a patient with cancer has the potential to selectively recognize his or her cancer.
• As cancers develop, they may respond to “immune pressure” in a number of ways. They can eliminate antigens through further mutation or deletion, a process termed “editing.” Although immune editing of tumors is well characterized in mouse cancer models, it has yet to be established in human cancers. Cancers can also resist immune elimination by inducing tolerance among tumor-specific T cells, which they achieve by co-opting natural self-tolerance mechanisms.
• A major focus of recent studies in cancer immunology is the immune microenvironment. Multiple cells and molecular interactions in the tumor microenvironment inhibit antitumor immune responses. These cells include regulatory T cells and myeloid-derived suppressor cells, which accumulate in tumors. Both cell types suppress cytotoxic T-cell responses that threaten tumors with destruction.
• In addition to suppressive cells, tumor cells and myeloid cells in the tumor microenvironment express ligands for inhibitory receptors expressed by effector T cells, termed “immune checkpoints.” The best-studied checkpoint expressed in the tumor microenvironment is the PD1 pathway. Many tumors express high levels of the PD1 ligands PDL1 and PDL2, whereas tumor infiltrating lymphocytes express high levels of PD1. These inhibitory ligand/receptor interactions are prime targets for antibody blockade.
• Certain chronic immune responses can promote cancer development. In particular, T-cell responses characterized by interleukin 17 (IL-17)–producing cells, termed T helper 17 (Th17) cells, are procarcinogenic. Th17 differentiation and IL-17 production depend on STAT3 signaling. The major antitumor immune response is a Th1 response, characterized by production of interferon-γ and driven by STAT1 and STAT4 activation. Th1 and Th17 development are mutually antagonistic. These contrasting immune responses explain how certain types of immune responses can inhibit cancer, whereas other types of immune responses can promote cancer development.
