4B_Tumor Antigens

Immune Response to Cancer: Tumor Antigens

Introduction

  • Focus on the interplay between cancer and the immune system, particularly the identification of tumor antigens.

  • Developed at Johns Hopkins Engineering.

Cancer Immunity Cycle

  • Priming and Activation:

    • Involves antigen-presenting cells (APCs) and T cells.

    • Activates the immune system to recognize cancer antigens.

  • Cancer Antigen Presentation:

    • Dendritic cells act as APCs to present tumor antigens.

  • Trafficking of T Cells:

    • T cells migrate from lymph nodes to the tumor site.

    • Involves the bloodstream and interactions with blood vessels.

  • Infiltration of T Cells into Tumors:

    • Cytotoxic T lymphocytes (CTLs) penetrate tumor tissues.

  • Recognition of Cancer Cells:

    • CTLs recognize tumor cells via specific receptors.

  • Killing of Cancer Cells:

    • Cytokine release leads to the destruction of cancer cells.

Reference: Chen et al. "Oncology Meets Immunology: The Cancer-Immunity Cycle". Immunity, 39.1 (2013): 1-10.

Classes of Tumor Antigens

  • Types of Tumor Antigens:

    • Oncoviral

    • Overexpression

    • Germ cell

    • Differentiation

    • Mutations

    • Abnormal posttranslational modification

Mechanisms of Immune Activation

Class of Tumor Antigens

  • Germ Cell:

    • Normally expressed in immune-privileged sites (e.g., testis).

  • Differentiation:

    • Antigens expressed in the original tissue of the tumor.

  • Overexpression:

    • Cancer cells express antigens at levels beyond normal tolerance thresholds.

  • Mutations and Abnormal Posttranslational Modifications:

    • Produce proteins that are foreign to the immune system.

  • Oncoviral:

    • Proteins from cancer-causing viruses (e.g., HPV).

Tumor Antigens: Mutations

  • Mechanisms:

    • Normal cells present self-peptides; mutations create new epitopes.

    • New epitopes increase vulnerability to T cell recognition.

Tumor Antigens: Normal Genes

  • Mechanisms:

    • Tumors may reactivate germ cell genes not typically expressed, presenting novel antigens.

    • Overexpressed self-proteins alter peptide presentation, leading to recognition by T cells.

Tumor Antigen Examples

Origins and Characteristics

  • Cyclin-dependent kinase 4:

    • Type: Cell-cycle regulator, Tumor type: Melanoma

  • Tumor-specific β-Catenin:

    • Type: Signal transduction relay, Tumor type: Melanoma

  • Caspase 8:

    • Type: Apoptosis regulator, Tumor type: Squamous cell carcinoma

  • Cancer-testis Antigens (MAGE-1, MAGE-3, NY-ESO-1):

    • Type: Normal testicular proteins, Tumor types: Melanoma, Breast Cancer, Glioma

  • Tyrosinase:

    • Type: Enzyme in melanin synthesis pathway, Tumor type: Melanoma

Another Set of Tumor Antigen Examples

Origins and Characteristics

  • HER-2/neu:

    • Receptor tyrosine kinase, Tumor types: Breast, Ovary

  • Wilms' Tumor:

    • Abnormal gene expression, Tumor type: Leukemia

  • MUC-1:

    • Underglycosylated mucin, Tumor types: Breast, Pancreas

  • Trp2 and GP100:

    • Types of abnormal post-transcriptional modifications, Tumor type: Melanoma

  • HPV Type 16, oncoviral proteins E6 and E7:

    • Tumor type: Cervical carcinoma

Cancer Immunity Cycle and Antigens

  • Combination of cancer antigens and damage-associated molecular patterns (DAMPs) with pro-inflammatory cytokines plays a crucial role.

Dendritic Cell Maturation

Stages

  1. Immature Dendritic Cells:

    • Arise from bone marrow, characterized by low MHC II expression and high intracellular MHC II.

    • Conditions affecting maturity: bacterial products, inflammatory mediators, cytokines, and DAMPs.

  2. Mature Dendritic Cells:

    • Found in lymphoid organs, have high surface MHC, and express co-stimulatory molecules (CD40, 80, 86).

    • Important for antigen presentation to T cells.

Conclusion

  • Tumor antigens play a vital role in the immune response to cancer, highlighting the potential for immunotherapies aimed at enhancing T cell recognition and destruction of cancer cells.