Tumor Immunology: Antigens & T-Cell Recognition

• Tumor specific antigens are unique to tumor cells and do not occur on normal cells.
• Tumor associated transplantation antigens (TAAs) are not unique to tumor cells.
• TAA's are expressed on normal cells during fetal development when the immune system is unable to respond and are not normally expressed in the adult.
• T cells recognize tumor antigens that fall into one of four categories:
  • Antigens encoded by genes selectively expressed by tumors
  • Antigens encoded by variant forms of normal genes, i.e., mutations
  • Antigens normally expressed only at certain stages of differentiation
  • Antigens that are already expressed in certain tumors.
• Lymphomas are solid tumors located in lymphoid tissues such as bone marrow and lymph nodes.
• Leukemias are composed of single cells that originate from the bone marrow and may include cells from either lymphoid or myeloid lineages.
• Some antigenic proteins on the surface of tumors are variant forms of normal proteins that were modified via a mutation in the gene encoding the protein.

Tumor Associated Antigens

• Unlike tumor specific antigens, tumor associated antigens are not unique to tumor cells.
• Tumor associated antigens are expressed on a cell type where it would not normally exist.
  • Examples: human breast cancer cells with high levels of growth factor curve two, map 1h, and gage two.
  • Other examples of oncogenes occur during fetal development and remain present in the testes during adulthood.

Oncogenes

• Cancer causing genes (oncogenes) are linked to retroviruses or RNA viruses.
  • Example: the viral oncogene src, or vsrc, from the rouse sarcoma virus which causes a malignant transformation when the virus enters a healthy cell.
• Viral oncogenes have counterparts in healthy cells referred to as proto oncogenes.
• The transformation of a proto oncogene to an oncogene can occur through mutations or dysregulation.

Oncogene Classifications

• Stimulators of cell division (e.g., SRC)
• Tumor suppressors (e.g., P53)
• Apoptosis regulators (e.g., BCL two)

Tumor Generation Summary

• Normal cells contain a gene sequence that translates into proteins.
• Normal cells present proteins using class one MHC molecules to the surface.
• Tumor specific antigens can be generated by gene incorporation, deletion, substitution, or modification due to external agents like environmental factors, viral infections, or radiation.
  • This leads to differential expression of proteins; instead of a target protein, an altered cell peptide is expressed.
  • This mutation or transformation from a normal cell into a cancer cell results in altered protein expression.
• Tumor associated transplantation antigens (TAAs) aren't unique to tumor cells but appear due to the expression of a new protein alongside existing normal proteins.
• Dysregulation of gene expression can also lead to tumor associated transplantation antigens where transcription factors are modified, resulting in over-expression of certain proteins
  • Alpha fetal peptide is an example and during fetal development.
• All cases require the processing of self peptides and presentation via class one MHC.

B Cell Tumors

• In many B cell tumors, oncogenes like myc and bcl-2 are translocated to immunoglobulin heavy chain loci, resulting in altered gene regulation.
• The MYC oncogene is often translocated to the immunoglobulin heavy-chain locus (IGH) in certain B cell lymphomas (such as Burkitt lymphoma), leading to overexpression of MYC and dysregulated cell growth.
• The BCL-2 gene, (involved in regulating apoptosis), is commonly translocated to the immunoglobulin heavy-chain (IGH) or light-chain loci in some B cell lymphomas (like follicular lymphoma), resulting in the overexpression of BCL-2, promoting cell survival and resistance to apoptosis.
• The immunoglobulin heavy-chain locus is highly active in B cells, especially during antibody production.
• MYC, a transcription factor that drives cell proliferation, gets overexpressed, leading to uncontrolled cell division.
• BCL-2 (an anti-apoptotic protein) overexpression prevents B cells from undergoing normal apoptosis, allowing them to survive longer and accumulate mutations.

Immunoglobulin

• Translocations don't initiate cancer, however they accelerate the growth and survival of already-transformed tumor cells by amplifying tumorigenic properties(growth, survival, and proliferation)

Class Tumor Antigens

• Tumor antigens are proteins or molecules expressed on the surface of tumor cells that can be recognized by the immune system as abnormal.
• Classified into two categories: tumor-specific antigens and tumor-associated antigens.

Tumor-Specific Antigens (TSAs)

• Unique to tumor cells (not expressed on normal cells).
• Typically caused by mutations in cancer cells' DNA, leading to neoantigens (novel protein sequences recognized as foreign).

Tumor-Associated Antigens (TAAs)

• Present in both normal and tumor cells, but at much higher levels in tumor cells, due to overexpression or loss of regulation.
• Tumor-associated antigens (TAAs) are molecules expressed by both normal and cancerous cells, but at higher levels in cancer cells.
  • Divided into: Overexpressed Proteins and Differentiation Antigens
• TAAs are expressed by cancer cells resulting from alterations in gene expression or post-translational modifications.
• Some TAAs play a role in promoting tumor growth and survival.
• Mechanism of Pathology: TAAs are expressed by cancer cells due to alterations in gene expression or post-translational modifications.
• Immuno-Pathophysiology:
  • TAAs are recognized by the immune system, leading to an immune response against cancer cells.
  • Tolerance mechanisms may exist, and the immune response may not always eliminate all cancer cells expressing TAAs.
• TSAs are unique to cancer cells (not expressed in normal, healthy cells).
  • Divided into: Neoantigens and Viral Antigens
• TSAs often arise from genetic mutations (point mutations, frame-shift mutations, or gene fusions).
• Not present in normal cells, making them specific markers for cancer.
• TSAs have high immunogenicity and are recognized as foreign by the immune system resulting in a strong immune response.