Intro to Cancer and Cancer Immunogenicity

Overview of Cancer Immunity

Antigen Recognition

Antigen Presentation

Effector T Cells Function

Immune Response to Tumors

Key Players in Immune Response:

  • Natural Killer (NK) cells

  • Cytotoxic T Lymphocytes (CTLs)

  • Macrophages

Immune Response Classification

Innate Immunity:

  • Born with it

  • Non-specific/broad specificity

  • Fast response

  • No memory present

Adaptive Immunity:

  • Acquired after birth

  • Very specific response

  • Lag phase before full response

  • Has memory to quickly respond to previously encountered antigens

Cytotoxic T Lymphocytes (CTLs) in Cancer Immunity

Activation Mechanism

The principal mechanism of immune protection against tumors is the killing of tumor cells by CD8+ CTLs.

Activation Process:

  • Cross Presentation:

    • Mechanism by which Dendritic Cells (DCs) activate naïve CD8+ CTLs specific for antigens from a third cell (e.g., tumor cell).

Function Post-Activation

Once differentiated into effector CTLs, they can migrate to any site where the tumor is growing and effectively kill the tumor cells.

T Helper Cells (Th1) in Cancer Immunity

Differentiation:

  • Driven by IL-12 secreted by DCs presenting tumor antigens to naïve CD4+ T cells in the lymph nodes.

Contributions to Anti-Tumor Response:

  • Secretion of IFN-γ:

    • Enhances CD8+ CTLs killing activity.

    • Activates macrophages and NK cells.

    • Increases MHC Class I expression on tumor cells, enhancing sensitivity to CTL lysis.

Natural Killer Cells (NK)

Overview

  • NK cells originate from lymphoid progenitors and are part of innate immunity.

  • They recognize altered cells (virally infected or cancer cells) through activating versus inhibitory receptors.

Role in Cancer Immunity

  • NK cells circulate in the blood and are recruited to tumor sites by IFN-γ.

  • They identify cancer cells through ligands (MIC-A, MIC-B) for activating receptor NKG2D.

  • Some tumors may downregulate MHC Class I molecule expression to evade CTL killing, making them good targets for NK cells.

  • NK cells can also be activated to kill antibody-coated tumor cells via Antibody-Dependent Cellular Cytotoxicity (ADCC).

Macrophages

Characteristics

  • Macrophages exhibit plasticity, acquiring different characteristics based on their environment—a feature currently under investigation for therapeutic strategies across multiple diseases.

Function in Cancer Immunity

  • Classical Activation (M1 Macrophages):

    • Activated by IFN-γ secreted by Th1 cells.

    • Identify tumor cells by recognizing 'danger signals' called Damage-Associated Molecular Patterns (DAMPs) released from dying tumor cells.

Tumor cell killing mechanisms include:

  • Direct release of harmful products.

  • ADCC.

  • Indirectly through recruiting CTLs.

Immune System as Promoter of Tumor Development

  • Mediated through tumor-derived factors.

  • Dendritic cells may be conditioned by tumors.

Resulting effects include:

  • Inhibition of tumor-specific effector T cells.

  • Stimulation of tumor growth via various pathways.

Evasion of Immune Responses by Tumors

Active Inhibition Methods:

  • Tumors may engage with T cell inhibitory molecules or create an immunosuppressive tumor microenvironment.

Immune Checkpoints

  • Immune checkpoints are crucial parts of the immune system that act as 'gatekeepers' to control immune responses.

  • Their roles include preventing autoimmunity and regulating responses to microbial infections.

Key immune checkpoints:

  • CTLA-4 (Cytotoxic T Lymphocyte Antigen-4):

    • Expressed on activated T cells and Tregs.

    • Suppresses T cell activation by competing with CD28 for binding to B7 proteins on Antigen-Presenting Cells (APCs).

    • Inhibition prevents T cell activation.

  • PD-1 (Programmed Cell Death Protein 1):

    • Expressed on activated T cells.

    • Interacts with ligands PD-L1 and PD-L2 on APCs.

    • When PD-1 binds its ligands, it triggers internal signaling pathways (phosphorylation events) that block activating signals from CD28 and the T Cell Receptor (TCR) complexes.

Tumor Adaptations

  • Tumor cells may upregulate PD-L1 and PD-L2 to inhibit tumor-infiltrating T cells.

  • Tumor-infiltrating T cells may present an 'exhausted' phenotype marked by upregulation of PD-1 and CTLA-4, contributing to an immunosuppressive environment.

  • Tumors may secrete immunosuppressive cytokines (e.g., TGF-β, IL-10) and enzymes that degrade immune components, such as perforin.

Immunosuppressive Tumor Microenvironment

  • Regulatory T cells (Tregs) may be present in tumor infiltrates, suppressing T cell responses.

  • Myeloid-derived suppressor cells (MDSCs) can build up in tumors and suppress both innate and T cell-driven immune responses. They do this by releasing immunosuppressive cytokines, encouraging the development of Tregs, and hindering differentiation of CTLs and Th1 cells.

  • M2 macrophages also may suppress anti-tumor activity in the immune landscape.

Failure to Produce Tumor Antigen

  • Rapid cell division and genomic instability in cancer cells lead to frequent mutations and deletions in genes encoding tumor antigens, potentially escaping immune recognition.

Immunoediting:

  • The immune response imposes selective pressure leading to the survival of tumor variants with reduced immunogenicity.

Characterized by three phases:

  • Elimination

  • Equilibrium

  • Escape

Failure to Present Tumor Antigens

  • Downregulation of MHC Class I expression on tumor cells reduces CTL recognition.

Mutations can affect:

  • MHC Class I molecules (HLA genes)

  • β2-microglobulin

  • Antigen-processing machinery components (proteasome, TAP)

  • Although MHC Class I loss may enhance NK cell recognition, additional mutations can arise to further block NK activity.