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.
• The definition of signaling pathways and molecules and cells that dampen antitumor immunity is leading directly to therapies for cancer. Anti-CTLA4 blocking antibodies have shown potent therapeutic effects in melanoma and anti-PD1 antibodies have shown potent responses in melanoma, renal cancer, and non–small cell lung cancer.
1. T cells can uniquely distinguish tumors from their normal cellular counterparts based on antigens generated by:
2. Immune/inflammatory promotion of carcinogenesis has been shown to be driven by:
3. Induction of tolerance to tumor antigens involves:
A Silencing of genes encoding tumor antigens
B Generation of idiotypic antibodies that block T-cell recognition of tumors
C Mutation of sites in genes encoding antigenic peptides strongly recognized by circulating T cells
D Presentation of tumor antigens by dendritic cells that have not been activated by pathogen-associated molecular patterns (PAMPs) or danger- associated molecular patterns (DAMPs)
E Generalized immunosuppression associated with dysregulated metabolism in the patient
4. Immune editing as a mechanism of immune resistance involves:
A Mutation or deletion of sites in genes encoding antigenic peptides strongly recognized by circulating T cells.
B Epigenetic silencing of genes encoding antigenic peptides strongly recognized by circulating T cells.
C Expression of ligands that bind inhibitory (checkpoint) receptors on T cells.
5. Which of the following is NOT an inhibitory (checkpoint) receptor on T cells?
1. Answer: D. Mutations generate novel sequences when they are nonsynonymous. Rearrangements generate novel sequences because the junctions produce novel sequences. T cells recognize peptides presented by major histocompatibility complex (MHC) (HLA in humans), and those peptides can be derived from any protein in the cell. Cancer-testes antigens are normally only expressed in germ cells, which express very low levels of MHC and thus effectively do not present antigen. Thus they are effectively not expressed in any normal cells in the host. Loss of silencing of cancer-testes antigens in the tumor as a result of epigenetic dysregulation therefore results in their expression uniquely in the tumor cell.
2. Answer: C. Th17 cell activation, typically at epithelial sites, has been shown in multiple animal models to drive inflammation-induced cancer formation. Neutralization of IL-17, the signature Th17 cytokine, or genetic knockout of the IL-17 gene reduces carcinogenesis in these systems.
3. Answer: D. Presentation of antigen by unactivated dendritic cells to T cells involves a paucity of co-stimulatory signals and cytokines necessary to activate T cells. In the absence of these signals, T cells default to an anergic state such that they do not mediate responses. This state is partially reversible by strong vaccines.
4. Answer: A. Immune editing refers to the elimination of specific unique antigenic sequences in tumors that allow the tumor to develop without recognition by T cells.
5. Answer: C. CD28 is a co-stimulatory receptor that enhances T-cell responses to antigen.
