Evading Immune Responses and Tumor Immunology Amy Lovett-Racke, PhD Associate Professor Department of Microbial Infection and Immunity

Cancer and Its Interactions with the Immune System Peter Parham The Immune System Third Edition Chapter 16 Cancer and Its Interactions with the Immune System Copyright © Garland Science 2009

Learning Objectives Know the difference in tumor-specific and tumor-associated antigens. Understand the evidence that the immune system limits the development of cancer. Compare and contrast the role of NK cells and CD8 T cells in the eradication of tumor cells. Understand the mechanisms of immune evasion by cancer cells.

Benign versus Malignant Tumors mutations – alterations in DNA tumor (swelling) = neoplasm (new growth) oncology – branch of medicine dealing with tumors Encapsulated, localized and limited in size. Can continue to grow by breaking through basal laminae and invading adjacent tissue.

Common Tissues of Cancer Origin in the USA Carcinoma – cancers of epithelial cells; Sarcoma – cancers of other cell types. Cancers of the Immune System Leukemia – cancer of circulating immune cells Lymphoma – solid lymphoid tumors Myeloma – tumor of plasma cells in bone marrow

Multiple Mutations are Required for Cancer Development Malignant transformation – when a cell has mutated such that it has become cancerous. Proto-oncogens – genes that normally contribute positively to the initiation and execution of cell division. Oncogenes – mutant forms of proto-oncogenes that contribute to malignant transformation. Tumor suppressor genes – encode proteins that prevent the unwanted proliferation of mutant cells.

Some Cancers are Associated with Viruses Mutagen – chemical or physical agent that damage DNA in such a way as to cause an increased rate of mutations. Carcinogen – mutagens that are known to increase the risk of cancer. Oncogenic virus – viruses that have the potential to transform cells and promote tumor formation.

Common Characteristics of Cancer Cells Immunosurveillence or Cancer Immunosurveillence – the ability of the immune system to detect and eliminate tumors at an early stage.

Rate of Growth of Cancer

MHC is Critical in Immune Recognition of Tumors Alloantigens – antigen that differs between members of the same species, such as HLA molecules. Alloantigens are recognized as foreign and elicit adaptive immune responses to eradicate the antigen.

Tumor-Specific Antigens Tumor-specific antigen – antigen expressed on tumor cells but not on normal cells. Tumor-associated antigen – antigen expressed on tumor cells but also found on normal cells, often in smaller amounts.

Antigens Commonly Mutated in Cancer

Generation of Novel Tumor Antigens

Evasion of the Immune Response by Tumors NK cell gd T cell MIC NKG2D

Evasion of the Immune Response by Tumors CD8 cancer cell CD8 T cell tumor antigen Cancer Cell

Evasion of the Immune Response by Tumors Tumor antigen Tumor antigen If a tumor antigen is presented by an activated macrophage or mature dendritic cell, B7 (CD80/86) will be present on the antigen presenting cells (APCs) and the tumor-specific CD8 T cell will be able to become activated and kill tumor cells. However, APCs are often not activated by tumors and therefore, the APCs remain in an immature or inactivated state. These APCs will not express the costimulator molecule B7 (CD80/86) and therefore, T cells specific for the tumor antigens will not become activated. They will become anergic or unresponsive, allowing the tumor to go undetected by CD8 T cells.

Evasion of the Immune Response by Tumors

Vaccination with Tumor Antigens

Monoclonal Antibodies Detect and Treat Cancer monoclonal antibody – antibodies produced by a single B cell clone and thus are all identical in structure and antigen specificity.

Monoclonal Antibodies Detect and Treat Cancer

Monoclonal Antibodies Detect and Treat Cancer

Monoclonal Antibodies Detect and Treat Cancer

Monoclonal Antibodies Detect and Treat Cancer

Things You Should Know Difference between tumor-specific and tumor associated antigens. Evidence that the immune response limits the development of cancers. Primary immune mechanisms to recognize and kill tumor cells CD8 T cells NK cells Mechanisms of immune evasions by cancers. Cleavage of Mic proteins on tumor cells and internationalization of NKG2D by NK cells and γδ T cells. Down regulation of MHC class I to evade CD8 T cells. Down regulation of tumor antigens so they are undetectable by CD8 T cells. Lack of costimulatory molecules on antigen presenting cells, resulting in anergic T cells. Recruitment of Tregs to the tumor environment, and production of cytokines (TGFβ and IL-10) to suppress antigen-specific T cells in the tumor environment.

Evading Immune Responses Quiz

Thank you for completing this module Questions? amy.lovett-racke@osumc.edu