Immune Response to Tumors: Tumor Antigens and Antitumor Immunity

00:01 So let’s turn now away from tumors of the immune system itself, and ask the question - does the immune system naturally prevent or attack cancers? Well the answer is yes, but perhaps only for certain cancers.

00:20 So what is the evidence that the immune system can actually recognize and attack cancers.

00:26 Well there’s an increased incidence of certain cancers in patients with immunodeficiency, including immunosuppressed transplant patients as we’ve just mentioned.

00:38 The term immunosurveillance is used.

00:41 And this relates to the concept that cells of the immune system patrol around the body looking for cells that have become abnormal because of malignant transformation.

00:53 Certainly the immune system can prevent tumors that are linked to oncogenic pathogens.

00:59 And it’s now known that a number of organisms can trigger the development of tumors.

01:06 So for example, the virus HTLV1 (Human T-cell Leukemia Virus-1) as the name suggests, is responsible for inducing T-cell leukemia.

01:17 Epstein-Barr virus can trigger a number of tumors including Burkitt’s lymphoma, nasopharyngeal carcinoma and post-transplant lymphoma.

01:28 The Human Papilloma viruses 16 and 18 are responsible for triggering cervical cancer and penile cancer.

01:37 Hepatitis B virus and Hepatitis C virus are linked to the development of liver cancer.

01:43 And the bacterium Helicobacter pylori can trigger the development of stomach cancer.

01:49 So it’s quite clear in these kind of situations where infectious agents are linked to the development of a tumor.

01:56 And after all the immune response has developed, has evolved to fight infectious agents.

02:02 One can see a clear potential role for the immune system in this kind of situation.

02:10 The term tumor antigen is used to describe antigens that are associated with tumor cells.

02:18 Remember, tumors are derived from normal cells.

02:25 Tumor-associated antigens are antigens that are present either in or on normal cells.

02:34 And the immune system will normally be tolerant to such antigens, because they’re normal self antigens.

02:42 In contrast, tumor-specific antigens are restricted to tumor cells, and the immune system may well not be tolerant to such antigens; perhaps arising by mutations in a gene that then encodes a different form of a protein to which the individual has not been made immunologically tolerant.

03:07 There are a number of different types of tumor antigen.

03:11 Some of the products have mutated oncogenes or tumor suppressor genes.

03:16 Examples of ongogene products include RAS mutations that are seen in around about 10% of human carcinomas, the p210 product of the Bcr/Abl rearrangements that can occur in chronic myeloid leukemia.

03:32 And mutations of tumor suppressor gene products, such a p53 mutations which are present in around about 50% of human tumors.

03:42 There are also tumor antigens that are unmutated but overexpressed products of oncogenes.

03:50 The HER2/Neu antigen is a good example of this that is seen in breast and other carcinomas.

03:58 Mutated forms of cellular genes that are not themselves actually involved in tumorigenesis, can act as tumor antigens.

04:05 For example, various mutated proteins that are found in melanomas that are recognized by cytotoxic T-lymphocytes.

04:13 And then we also have the products of genes that are silent in most normal tissues.

04:18 For example, the cancer/testis antigens expressed in melanomas and many carcinomas.

04:24 These antigens are normally expressed mainly in the testis and placenta, but can get expressed in tumor cells.

04:32 Tumor antigens can also be normal non-oncogenic proteins that are overexpressed in tumor cells.

04:38 For example, tyrosinase, gp100, and the MART antigens that are found in melanomas and are normally expressed in melanocytes.

04:50 They can be the products of oncogenic viruses.

04:52 For example, the papilloma virus E6 and E7 proteins that are associated with cervical carcinomas.

05:00 EBNA-1 protein of Epstein-Barr virus, present in EBV-associated lymphomas and in nasopharyngeal carcinoma.

05:10 Oncofetal antigens, such as the carcinoembryonic antigen that’s present in many tumors, and also expressed in liver and other tissues during inflammation.

05:22 And another example of an oncofetal antigen is alphafetoprotein.

05:28 Glycolipids and glycoproteins can also act as tumor antigens.

05:32 For example, the GM2 and GD2 antigens on melanomas.

05:38 And then finally, differentiation antigens that are normally present in the tissue of origin.

05:44 For example, the prostate specific antigen (PSA) present in prostate carcinomas.

05:49 And another example here would be CD20 on B-cell lymphomas.

05:55 Anti-tumor immunity is essentially the same kinds of responses that we see against infectious agents.

06:02 So antibody together with complement, the antibody can bind to tumor antigens present on the surface of the tumor cell, activate complement.

06:12 And the membrane attack complex can destroy the tumor cell.

06:17 Antibody dependant cellular cytotoxicity (ADCC), again an antibody against a tumor antigen expressed on the surface of the tumor cell can be recognized by cells that are capable of mediating ADCC.

06:33 We call such cells, killer cells; really they can be any cell in the immune system that has an Fc receptor and also is able to fuse toxic molecules.

06:43 And most cells in fact in the immune system can carry out this function of ADCC.

06:48 There can be direct natural killer cell cytotoxicity, where the killer activating receptors on the surface of natural killer cells recognize ligands on the surface of the tumor cell.

07:03 And finally there can be cytotoxic T-cells which recognize tumor-derived peptides presented by MHC Class I molecules.

07:13 It’s very clear that immune system cells are naturally present within tumors.

07:18 We can find T-cells, natural killer cells, macrophages, also regulatory T-cells and myeloid derived suppressor cells within tumors.

07:33 So T-cells, natural killer cells and macrophages potentially could mediate a beneficial anti-tumor response.

07:41 One of the problems is that very often, these other cell types, such as regulatory T-cells and myeloid derived suppressor cells actually dampen down the anti-tumor response.