Cancer Immunology and Immunotherapy: Microbiology & Immunology AP0506 Study Notes

Cancer Immunology and Immunotherapy

Introduction to Cancer and Immune Regulation

Cancer arises when the balance between cell renewal and cell death is disrupted, leading to uncontrolled cell growth. The immune system plays a crucial role in recognizing and eliminating cancerous cells, but tumors can develop mechanisms to evade immune detection.

• Cell Cycle Control (Cell Birth): Regulates cell proliferation through tightly controlled checkpoints.

• Apoptosis Control (Cell Death): Ensures removal of damaged or unnecessary cells.

• Net Cell Growth: Determined by the balance between cell birth and cell death.

Cellular Growth Control

Cellular growth is regulated by external signals (growth factors) that bind to cell surface receptors, initiating signal transduction pathways and activating gene expression for DNA replication and cell division.

• Growth Factors: Proteins that stimulate cell proliferation.

• Signal Transduction: Cascade of intracellular events leading to gene activation.

• Gene Expression: Drives cell cycle progression and differentiation.

Oncogenes and Tumor Suppressor Genes

Mutations in specific genes can disrupt growth control, leading to cancer. These genes are classified as:

• v-onc (virus oncogenes): Oncogenes introduced by viruses.

• c-onc (cellular oncogenes): Normal genes that can become oncogenic when mutated.

• Proto-oncogenes: Stimulate cell proliferation; mutations convert them to oncogenes.

• Tumor Suppressor Genes: Inhibit cell proliferation and regulate apoptosis.

Multiple mutations are often required for cancer development, depending on cell type and mutation nature.

Immune Surveillance and Tumor Antigens

The immune system can recognize and eliminate cancer cells through both humoral and cell-mediated responses. Tumor antigens recognized by T cells include:

• Antigens only expressed by tumors

• Mutated normal antigens

• Antigens expressed at inappropriate stages of cell growth

• Overexpressed antigens

Tumor-specific transplantation antigens (TSTA) and tumor-associated transplantation antigens (TATA) are key targets for immune recognition.

T Cell Recognition of Tumor Antigens

T cells recognize processed antigens presented by MHC molecules on antigen-presenting cells (APCs). This is more effective in hematopoietic cancers than in solid tumors due to differences in antigen presentation and immune cell access.

• Hematopoietic Cancers: Naive T cells encounter cancerous blood cells; higher rates in immunosuppressed individuals.

• Solid Tumors: Limited T cell access; tumor cells may lack co-receptors or downregulate MHC, impeding recognition.

Role of Regulatory T Cells (Tregs) and Virus-Associated Tumors

Viruses that establish chronic infections can cause cancer by evading immune responses. In cancer, Tregs suppress anti-tumor immunity, facilitating tumor escape. However, in some cancers with strong inflammatory infiltrates, Tregs may reduce bystander tissue damage.

Innate Immune Recognition: Macrophages and NK Cells

Innate immune cells can recognize and destroy tumor cells:

• Macrophages: Detect abnormal surface molecules (e.g., phosphatidylserine); produce TNF-α to induce tumor necrosis.

• Natural Killer (NK) Cells: Target cells with low MHC I expression or abnormal proteins; recruited by macrophage-derived signals.

Antibody Responses to Tumor Antigens

Tumor-specific antibodies can induce cell death via complement activation or antibody-dependent cell-mediated cytotoxicity (ADCC). However, most evidence for their effectiveness is from in vitro studies, with limited in vivo efficacy.

Tumor Evasion of the Immune System

Tumors can evade immune detection by:

• Downregulating MHC I expression (via viral or selective pressures)

• Providing poor co-stimulation (lack of co-stimulatory molecules or APCs)

• Modulating antigens to avoid antibody or T cell recognition

Some anti-tumor antibodies may paradoxically enhance tumor growth by blocking T cell responses or inducing antigen shedding.

Cancer Immunoediting

The interaction between tumors and the immune system can be described in three phases:

• Elimination: Immune system destroys tumor cells (immunosurveillance).

• Equilibrium: Immune system selects for tumor variants with increased survival capacity.

• Escape: Tumor variants evade immune control and proliferate uncontrollably.

Immunotherapy Strategies

Immunotherapy aims to enhance the immune system's ability to detect and destroy cancer cells. Approaches include:

• General Immune Boost: Use of adjuvants or cytokines.

• Specific Activation: Vaccines targeting tumor antigens.

• Immune-Related Weapons: Monoclonal antibodies, lymphocytes (T cells, NK cells), and phagocytes (macrophages).

Monoclonal Antibodies in Cancer Therapy

Monoclonal antibodies are engineered to bind specific tumor antigens, with effector functions determined by their Fc region. Production involves immunizing animals, fusing B cells with myeloma cells, and selecting clones producing the desired antibody.

Type	Human Content	Suffix	Immunogenicity
Murine	0%	-omab	High
Chimeric	65%	-ximab	Moderate
Humanized	>90%	-zumab	Low
Fully Human	100%	-umab	Lowest

Examples of Monoclonal Antibodies

• Rituximab (Rituxan): Targets CD20 on B cells in Non-Hodgkin's lymphoma; induces cytotoxicity via ADCC or complement.

• Trastuzumab (Herceptin): Targets HER2 in breast cancer; blocks growth signaling and induces immune-mediated cell death.

• Gemtuzumab ozogamicin (Mylotarg): Targets CD33 in acute myeloid leukemia; delivers cytotoxic agent to induce apoptosis.

• J591: Targets PSMA in prostate cancer; used for radioimmunotherapy.

Checkpoint Inhibitors

• Ipilimumab (Yervoy): Blocks CTLA-4, enhancing T cell activation; used in melanoma and other cancers.

• Nivolumab and Pembrolizumab: Block PD-1/PD-L1 pathway, preventing T cell inhibition and promoting anti-tumor responses.

Cancer Vaccines

Cancer vaccines aim to induce immune responses against tumor-specific or tumor-associated antigens. They are most effective as preventive measures or in combination with other therapies.

• HPV Vaccines: Prevent cervical cancer by targeting HPV16 and HPV18.

• Experimental Vaccines: Target antigens not normally expressed on somatic cells (e.g., embryonic antigens, mutated proteins, viral antigens).

Adoptive Cell Transfer and Engineered T Cells

Adoptive transfer involves expanding tumor-specific T cells ex vivo and reinfusing them into patients. Engineered T cells, such as CAR-T cells, are genetically modified to recognize tumor antigens and have shown promise in treating hematological malignancies.

• CAR-T Cells: Chimeric antigen receptors enable T cells to recognize antigens independently of MHC.

• NK Cell Therapy: CAR-engineered NK cells are being developed for solid and hematological tumors.

Cytokine Therapy

Cytokines such as interferons and interleukins can enhance anti-tumor immunity but may cause significant side effects. Local administration or gene therapy approaches are being explored to minimize toxicity.

• Interleukin-2 (IL-2): Activates T cells and NK cells; toxic at high doses.

• Interferons (IFN-α, β, γ): Increase MHC expression, inhibit cell division, and enhance immune cell activity.

• Tumor Necrosis Factor (TNF): Induces tumor cell death and inhibits angiogenesis.

Unintended Consequences and Future Directions

Immunotherapies can cause immune-related adverse effects, sometimes severe. Ongoing research aims to optimize efficacy while minimizing toxicity. Advances in gene editing and engineered cell therapies hold promise for more effective and safer cancer treatments.

Summary

• Immune responses are generally effective against tumors, but some cancers evade detection.

• Immunotherapy strategies include monoclonal antibodies, checkpoint inhibitors, vaccines, and adoptive cell transfer.

• Understanding tumor-immune interactions is key to developing more effective therapies.