BIOS5050 Week 29 - Tumour Immunology_JK_2025

Tumour Immunology I

Covers fundamental aspects of cancer and emphasizes the evidence regarding immune responses to tumors. The course specifically focuses on Tumour-specific antigens (TSA) and Tumour-associated antigens (TAA).

Cancer Development

Cancer originates from a multidimensional process characterized by a gradual build-up of mutations over time. The stages of tumor formation typically begin with:

  • Adenomatous polyps: These can range in size (large, small) and may include hyperproliferative types that exhibit severe dysplasia, signaling a precancerous stage.

  • The progression of benign tumors can ultimately lead to malignant cancers such as adenocarcinoma.

Key mutations associated with cancer include:

  • Activation of K-ras: A common alteration that promotes cell proliferation.

  • Loss of tumour suppressor genes: Key genes such as those located at 18q (TSG), APC (Adenomatous polyposis coli), and p53, which play crucial roles in regulating the cell cycle and preventing tumor development.

Tumour Composition

Tumors are heterogeneous structures formed by a variety of cell types:

  • Hematopoietic Origin: Comprises immune cells like granulocytes, natural killer (NK) cells, T cells, B cells, macrophages, dendritic cells, and regulatory T cells (Tregs).

  • Mesenchymal Origin: Includes fibroblasts and pericytes, which contribute to the tumor architecture.

Immune Cell Presence in Tumours

Despite the infiltration of immune cells within tumor microenvironments, tumors are often able to evade immune destruction, facilitating continued growth. The types of immune cells present include:

  • CD8+ T cells (Cytotoxic T Lymphocytes, CTL) marked in pink, responsible for direct killing of cancer cells.

  • CD4+ T cells (T Helper cells, TH) represented in brown, assisting in orchestrating the immune response.

  • FOXP3+ Tregs (Regulatory T cells) depicted in green, which can suppress immune responses.

  • CD20+ B cells shown in blue, involved in antibody production and antigen presentation.

Immune Infiltrates and Prognosis

The type, nature, and extent of immune cell infiltrates are critical prognostic factors that significantly influence the outcome of solid tumors.

Hallmark of Cancer: Avoiding Immune Destruction

Key characteristics of cancer include a range of mechanisms that enable tumors to evade immune detection such as:

  • Deregulating cellular energetics leading to altered metabolism.

  • Resisting cell death through various survival signals.

  • Genome instability and mutation generating variability among tumor cells.

  • Sustaining proliferative signaling via autocrine or paracrine signaling pathways.

  • Evading growth suppressors, which normally would halt the proliferation of abnormal cells.

  • Inducing angiogenesis to ensure an adequate blood supply.

  • Activating invasion and metastasis, allowing cancer to spread to distant sites.

  • Enabling infinite replicative immortality, allowing continuous division without senescence.

  • Tumor-promoting inflammation, which can aid in creating a supportive microenvironment for tumor growth.

Immune Status and Tumour Susceptibility

Research indicates that the immune status of hosts, particularly in mouse models, is a key factor influencing susceptibility to tumors initiated by chemical carcinogens.

Risk of Tumours in Immunosuppressed Patients

Immunosuppressed patients are at significantly heightened risk for various types of tumors. Relative risks associated with tumor types include:

  • Kaposi's sarcoma: 50-100 times risk increase.

  • Non-Hodgkin's lymphoma: 25-45 times.

  • Carcinoma of the liver: 20-35 times.

  • Carcinoma of the skin: 20-50 times.

  • Carcinoma of the cervix: 2.5-10 times.

  • Melanoma: 2.5-10 times.

  • Lung carcinoma: 1-2 times.

Tumour Diversity and Immunity

Tumors manifest a remarkable degree of antigenic diversity. Studies involving mice injected with irradiated tumor cells have revealed that these animals can develop immunity against identical viable tumor cells but not against different cell types from the same strain, emphasizing the concept of antigen specificity in immune responses against tumors.

Overview of Tumour Immunology I

A comprehensive review of cancer fundamentals alongside the evidential basis of immune response efficacy against tumors. Key elements include an in-depth examination of Tumour-specific antigens (TSA) and Tumour-associated antigens (TAA).

Tumour-Specific Antigens (TSA)

TSA are unique to tumor cells and arise from somatic DNA mutations leading to the expression of novel protein forms. Additionally, some TSA can be products of viral infections, making them essential targets for the immune system's cytotoxic T cells, as they are presented by Major Histocompatibility Complex (MHC) Class I molecules.

Tumour-Associated Antigens (TAA)

Unlike TSA, TAA are not exclusive to tumor cells and can also be found at lower expression levels in normal healthy tissues. An example includes proteins associated with embryonic development, such as carcinoembryonic antigens, which may be re-expressed in certain tumor types.

Categories of Rejection Antigens

The tumor-associated rejection antigens fall into six categories, including:

  1. Neoantigens arising from somatic mutations.

  2. Germ cell antigens (e.g., MAGE family).

  3. Tissue-restricted differentiation antigens.

  4. Abnormal gene expression products.

  5. Post-translationally modified antigens.

  6. Antigens derived from oncogenic viruses.

Immune Recognition of Tumour Antigens

Insights from patient tumor types provide evidence that specific proteins are selectively recognized by T cells, underlining the significance of immunogenicity in cancer therapy.

Neoantigen Correlation with Tumour Mutations

A direct correlation exists: an increase in mutations within tumors tends to correspond with a greater in number neoantigens. This effect has been documented in various cancer types, such as melanoma, lung cancer, and MMR-deficient colorectal cancer.

Summary of Immune Recognition of Cancer

The immune system maintains the potential to identify and mount a response against cancerous cells via the recognition of aberrant proteins and stress signals. While TAAs possess lesser specificity in contrast to TSAs, their ubiquitous presence in normal cells complicates tumor immunology.

Tumour Immunoediting

This concept illustrates how the immune system actively shapes the evolution of tumors through persistent selection pressure.

Additional Notes on Immune Evasion Mechanisms

  • Tumor cells may utilize various strategies for immune evasion, including the down-regulation of MHC Class I expression, which is critical for T-cell targeting.

  • Natural Killer (NK) cells play a crucial role in identifying and targeting tumor cells lacking MHC I, facilitating immune surveillance despite the tumor's attempts to evade detection.

These mechanisms form the basis of potential therapeutic interventions in cancer treatment, aiming to enhance immune responses against malignancies.