Cancer and the Immune System

Tumour or Neoplasm

Cells that expand in an uncontrolled manner will produce a…

Benign Tumours

are incapable of indefinite growth and do not invade surrounding healthy tissue

Malignant Tumours

continue to grow and become progressively more invasive and spread (metastasize) to other tissues

Malignant Transformations

Mutations in genes regulating cell division can lead to unregulated cell growth":

• Cells can be transformed by various chemicals (e.g., pesticides), physical agents (e.g., asbestos), ionizing radiation, or viral infections

• Agents that induce DNA mutations and lead to unregulated cell proliferation are carcinogens

Cancer-Associated Genes

Genes that have been associated with cancer control cell proliferation and survival

Oncogenes

encourage growth and proliferation; they promote cancer when their activity is increased

Tumor-suppressor Genes

inhibit proliferation or mediate DNA repair; their failure allows cancer cell survival

Apoptosis Genes

enforce or inhibit cell death signals, thereby controlling programmed cell death

Blood-Cell Cancers

• Lymphomas, myelomas, and leukemias are blood cell cancers derived from hematopoietic stem cells (HSCs)

• They are distinguished by stage of development

Leukemia

• Arises from cells in early development in the bone marrow

• Can be classified as either myelogenous or lymphocytic depending on which branch is affected

• When untreated, may be acute or chronic

  • acute – appears suddenly and progresses rapidly; permanent remission is possible

  • chronic – develops slowly and is somewhat asymptomatic; more difficult to eradicate and patients may live with the disease for long periods of time

Lymphomas

• arise after progenitors have left bone marrow

• spread through the lymphatic system

• proliferate in secondary lymph organs; swollen lymph nodes are common early symptoms

Myelomas

• arise after progenitors have left bone marrow

• arise from uncontrolled proliferation of fully differentiated B cells

• spread through the blood; migrate to bone marrow

• produce a mutated form of antibody called M protein

Cancer Hallmarks

• Six original defining characteristics:

  • Sustaining proliferative signalling

  • Evading growth suppressors

  • Activating invasion and metastasis

  • Enabling replicative immortality

  • Inducing angiogenesis

  • Resisting cell death

• Focus on essential cellular processes

• Four enabling characteristics were added to describe microenvironmental influences:

  • Cancer stem cell (CSC)

  • Invasive cancer cell

  • Cancer cell (CC)

  • Immune inflammatory cells (ICs)

Tumour Antigens

• Neoplastic cells are still self cells with self antigens, but they may also express unique antigens

• Unique tumour antigens include:

  • proteins exclusively expressed by infected tumour cells

  • novel peptides generated by mutations

  • proteins inappropriate for the current developmental stage

  • overexpressed wild-type self proteins

Tumour-specific antigens (TSAs)

• Unique sequences that result from infection or DNA mutations that generate altered proteins (neoantigens)

• Do not occur on normal cells in the body

Tumour-associated antigens (TAA)

• Not unique to tumour cells (variant forms of normal genes)

• Temporal displacement of gene expression (e.g., oncofetal tumour antigens)

• High expression of low level protein

Oncofetal Tumour Antigens

• Proteins that are typically expressed during embryonic or fetal development before the immune system is immunocompetent

  • Their later expression induces an immunologic response!

• α-fetoprotein (AFP) – the most abundant fetal protein; significantly elevated levels in nonpregnant adults are symptoms of liver, ovarian, and testicular cancer

• Carcinoembryonic antigen (CEA) – found in GI/liver cells of 2- to 6-month-old fetuses; 90% of patients with advanced colorectal cancer and 50% with early colorectal cancer have increased CEA

The Immune Response to Cancer

Three proposed pathways for how the immune system controls or inhibits cancer:

1. Destroying viruses that are known to transform cells

2. Eliminating all pathogens and downregulating inflammation

3. Identifying and eliminating pre-cancerous and transformed cells – immunosurveillance

Immunoediting

Immunoediting both protects against and promotes tumour growth:

• Anti-tumour responses select for toughest cells

• Three phases proposed:

1. Elimination

2. Equilibrium

3. Escape

Elimination

identifying and attacking the cells that can be targeted

Equilibrium

a state of balance between the destruction of some tumour cells, and the survival of the “best” tumour cells

Escape

the most aggressive and least immunogenic cells thrive and spread

Tumour specific antibodies:

• Sometimes block CTL access

• Ab-Ag complexes can block Fc receptors (e.g., on NK cells

Tumour specific CTLs:

Problem: many tumours down-regulate MHC

NK cells and Macrophages

• Can carry out ADCC

• NK cells use surface receptors that respond to activating and inhibiting signals delivered by self cells

• Not restricted by MHC molecules

A tumour downregulates MHC class I expression. Which immune response is most likely to remain effective?

Natural Killer (NK) cell-mediated immunity

A tumour is initially well-controlled by CD8⁺ T cells but later becomes resistant despite a strong immune response. Which change most directly explains this shift?

the differentiation of CD8⁺ T cells into a state of terminal exhaustion

Inflammatory Responses can Promote Cancer

Chronic inflammation:

• Increases cellular stress signals

• Can lead to genotoxic stress (e.g., ROS)

• Increasing mutation rates in cells

• Growth factors/cytokines released by cells often induce proliferation

• Inflammation is pro-angiogenic and pro-lymphangiogenic

  • increases growth of blood and lymphatic vessel growth, allowing for greater tumour-cell invasion into surrounding tissues

Immunosuppression in the Tumor Microenvironment

• Soluble factors can suppress immunity to form a tumour (immune) microenvironment (TME or TIME)

• e.g.,

  • TGF-β inhibits TH1 responses and promote other helper types (TH17 and TREG)

  • IL-10 can promote tumours and induce tolerance or encourage innate immune responses

• Suppression prevents antitumour activities of immune cells

Reduced MHC expression in tumour cells:

• Tumour cells with mutations in genes for MHC class I make poor CTL targets

• Mutations in TAP, β2-microglobulin, and IFN-γ signaling can lead to insensitivity

Decreased expression of NK-activating receptor ligands:

makes cells with low MHC class I expression poor targets for NK cells

Tumour-cell resistance to apoptosis:

can occur by expression of mutated or absent death receptors, upregulation of anti-apoptotic mediators or downregulation of pro-apoptotic mediators

Tumour cells provide poor costimulatory signals:

Lack of a proper second signal may lead to clonal anergy in T cells and immune tolerance to cancer cells

A tumour expresses normal levels of antigen but fails to activate T cells. What is the most likely explanation?

a lack of costimulation or the presence of an immunosuppressive tumor microenvironment (TME)

Cancer Therapies

• Surgical removal (resection) and radiation are commonly used for solid tumours

  • Adjuvant cancer therapy adds drugs or small molecule inhibitors

  • Neoadjuvant cancer therapy starts with drugs and follows with surgery

• Drug therapies generally fall into four loosely organized categories:

  • chemotherapies – aimed at blocking DNA synthesis and cell division

  • hormonal therapies – interfere with tumour-cell growth

  • targeted therapies – small molecule inhibitors for tumours that are sensitive to the drugs

  • immunotherapies – induce or enhance the antitumor immune response

Monoclonal Antibodies (mAbs)

Initially intended to deliver toxin or activate immune pathways (e.g., complement, ADCC, ADCP)

Successes include:

• Treatment of terminal B-cell lymphoma with anti-idiotype mAb

• mAb against CD20 B-cell marker for non-Hodgkin’s lymphoma and chronic lymphocytic leukemia (CLL)

• Antibody-drug conjugates that couple toxic molecules with mAb

• mAb against receptors

Bispecific T-Cell Engagers (BiTEs)

• recognize two target epitopes

• activate T cells

• are made by combining light- and heavy-chain variable regions of two antibodies into a single chain

Immune Checkpoint Blockades

• Ipilimumab is a monoclonal antibody against CTLA-4

• It is an immune checkpoint inhibitor (ICI) that employs immune checkpoint blockage (ICB)

• Originally licensed for use against malignant melanoma

Cancer Immunotherapies

1. Monoclonal antibodies

2. Immune checkpoint blockade

3. Transferred T cells

4. Cancer Vaccine