8 tumours, immunosurveillance Flashcards
What are the three leading causes of death in industrialized nations?
Cardiovascular diseases
Infectious diseases
Cancer
How do tumours arise?
Cancer/tumours originate from a single transformed cell that undergoes uncontrolled proliferation and ignores signals from neighbouring cells.
What is metastasis?
The process by which cancer cells detach, migrate to new locations via blood/lymph, and establish secondary tumours.
How do cancer cells lose their adhesion properties?
They lose surface molecules that normally keep them in place, enabling detachment and metastasis.
Why is complete tumour removal crucial in treatment?
Because even a small number of residual tumour cells (minimal residual disease) can lead to recurrence.
What is the immunosurveillance theory?
The idea that the immune system constantly monitors and destroys spontaneously arising tumours.
What is an example of evidence supporting immunosurveillance?
Increased tumour incidence in immunosuppressed individuals (e.g. transplant recipients, HIV-infected patients).
Why do transplant recipients have a higher tumour risk?
They take immunosuppressive drugs, reducing immune surveillance, allowing tumour growth.
List some virus-associated cancers seen in transplant recipients.
Kaposi’s sarcoma (HHV-8)
Non-Hodgkin’s lymphoma (EBV)
Liver carcinoma (Hepatitis B/C)
Cervical carcinoma (HPV)
How does HIV increase cancer risk?
HIV weakens the immune system, reducing its ability to suppress oncogenic viruses and tumour cells.
Why do some tumour variants escape immune destruction?
Tumours mutate over time, evolving resistance to immune attack and recruiting regulatory cells for protection.
What are tumour antigens?
Molecules preferentially expressed by tumour cells that can be recognized by immune cells.
List the types of tumour antigens.
Strictly tumour-specific
Expressed by stem cells but aberrantly in tumour cells
Tissue-specific differentiation antigens
Overexpressed normal antigens
Abnormally post-translationally modified proteins
Viral oncogene-encoded antigens
How can tumour antigens aid in cancer diagnosis?
Measuring antigen levels in serum (e.g., PSA for prostate cancer).
Detecting metastases in stained tissue samples.
How do tumours evade immune detection?
Loss of MHC expression → T cells fail to recognize them.
Production of immunosuppressive cytokines (e.g., TGF-β, IL-10).
Antigen loss or alteration to escape immune recognition.
Lack of costimulatory molecules → no proper T cell activation.
What is the impact of low immunogenicity on tumour survival?
Tumours without MHC ligands, adhesion, or costimulatory molecules are less likely to be targeted by the immune system.
How do tumours induce immune suppression?
Secretion of factors like TGF-β, IL-10, and IDO, which inhibit T cell activation.
Expression of PD-L1, which suppresses T cell activity.
What are the two main approaches to cancer immunotherapy?
Non-specific immune activation
Targeted (specific) immunotherapies
Who was William Coley and what did he discover?
He observed cancer remission following bacterial infections, leading to the use of bacterial toxins (Coley’s toxin) for immune stimulation.
What is BCG therapy?
Bacillus Calmette-Guérin (BCG) is injected into the bladder to stimulate the immune response against bladder cancer.
What is a monoclonal antibody?
A laboratory-made antibody that binds specifically to tumour antigens, marking them for immune destruction.
How do monoclonal antibodies work in cancer therapy?
They activate natural killer (NK) cells via Fc receptors (ADCC).
Can be conjugated with toxins/radiation for targeted tumour destruction.
Give an example of a monoclonal antibody used in cancer therapy.
Rituximab: Binds CD20 on Non-Hodgkin lymphoma cells, leading to immune-mediated destruction.
What are checkpoint inhibitors?
Antibodies that block immune checkpoints (e.g., CTLA-4, PD-1) to enhance T cell activity against tumours.
Give an example of a checkpoint inhibitor.
Ipilimumab (anti-CTLA-4) → enhances T cell activation.
How does PD-1 blockade work in immunotherapy?
Prevents tumours from suppressing T cells, allowing them to attack cancer cells.
What is the goal of therapeutic cancer vaccines?
To stimulate tumour-specific immune responses after cancer diagnosis.
What is Prostvac?
A therapeutic vaccine for prostate cancer using recombinant vaccinia expressing PSA.
What were the clinical results of Prostvac trials?
Phase II: Increased median survival by 8.5 months.
Phase III: Results were disappointing; now tested with checkpoint inhibitors.
What is Provenge (Sipuleucel-T)?
An autologous dendritic cell-based therapy for prostate cancer.
What is the major drawback of Provenge?
High cost ($100,000 per patient) for a modest survival benefit (4.1 months).
What does CAR-T stand for?
Chimeric Antigen Receptor T cell therapy.
How does CAR-T cell therapy work?
T cells are engineered to express a receptor targeting a specific tumour antigen and reinfused into the patient.
What is the primary antigen targeted in CAR-T therapy for B cell cancers?
CD19.
What are some advantages of CAR-T therapy?
Highly specific tumour targeting.
Not restricted by MHC alleles.
What is a major limitation of CAR-T therapy?
Potential for severe immune-related side effects like cytokine release syndrome (CRS).
What cancers have seen remission with CAR-T therapy?
Acute lymphoblastic leukaemia (ALL).
Non-Hodgkin lymphoma.
Chronic lymphocytic leukaemia.
What are ‘magic bullets’ in cancer therapy?
Antibodies conjugated with toxins/radioisotopes that specifically kill tumour cells
Why do monoclonal antibodies sometimes fail?
Poor tumour penetration.
Binding to normal cells with the same antigen.
Circulating antigen ‘mopping up’ antibodies.
What are the key challenges in developing a cancer vaccine?
Tumour antigen variability.
Immune tolerance to self-antigens.
Tumour immune evasion mechanisms.
What additional experimental evidence supports immunosurveillance?
Knockout mice lacking key immune components (e.g., IFN-γ, perforin, or NK cells) develop tumours at a higher rate than normal mice.
How do tumour-infiltrating lymphocytes (TILs) provide evidence for immunosurveillance?
Higher levels of TILs in a tumour correlate with better patient prognosis, suggesting the immune system actively fights tumours.
What are PD-1 and PD-L1, and how do they relate to cancer?
PD-1 (on T cells) binds PD-L1 (on tumour cells) to suppress immune responses, allowing tumours to evade detection.
What are examples of PD-1 and PD-L1 inhibitors used in immunotherapy?
Nivolumab and Pembrolizumab (anti-PD-1)
Atezolizumab and Durvalumab (anti-PD-L1)
How do PD-1/PD-L1 inhibitors work?
They block PD-1/PD-L1 interactions, restoring T cell activity against tumours.
What are BiTEs (Bispecific T-cell Engagers)?
Engineered antibodies that bind both T cells (via CD3) and tumour cells (via tumour-specific antigen) to promote targeted killing.
How do mRNA cancer vaccines work?
They encode tumour-specific antigens, prompting the immune system to recognize and destroy cancer cells.
What role do NK (Natural Killer) cells play in cancer therapy?
NK cells can kill cancer cells without prior sensitization. CAR-NK therapies are being developed as an alternative to CAR-T cells.
What is the tumour microenvironment (TME)?
The ecosystem around a tumour, including immune cells, fibroblasts, blood vessels, and extracellular matrix.
How does the TME suppress immune responses?
Secretes immunosuppressive cytokines (e.g., TGF-β, IL-10)
Induces hypoxia (low oxygen), which alters immune cell function
Recruits regulatory T cells (Tregs) to inhibit anti-tumour immunity
What is the Warburg effect?
Cancer cells preferentially use aerobic glycolysis (even in oxygen-rich conditions) to generate energy, supporting rapid proliferation.
What are the major side effects of CAR-T cell therapy?
- Cytokine Release Syndrome (CRS): Overproduction of inflammatory cytokines, leading to fever, hypotension, and organ dysfunction.
- Immune Effector Cell-Associated Neurotoxicity Syndrome (ICANS): Neurological side effects, including confusion, seizures, and coma.
Why do CAR-T therapies work better for blood cancers than solid tumours?
Solid tumours have dense stroma, making it hard for CAR-T cells to infiltrate.
The tumour microenvironment suppresses T cell function.
What strategies are being tested to improve CAR-T therapy for solid tumours?
Engineering CAR-T cells to resist immunosuppressive signals.
Adding chemokine receptors to enhance tumour infiltration.
Combining CAR-T cells with checkpoint inhibitors (e.g., anti-PD-1).
What are the three phases of cancer immunoediting?
Elimination (Immunosurveillance)
Equilibrium (Tumour Dormancy)
Escape (Tumour Progression)
what is elimination?
The immune system detects and destroys cancer cells.
Key players: NK cells, CD8+ T cells, macrophages, dendritic cells.
Mechanisms: Cytotoxicity (granzyme/perforin), IFN-γ release, and FasL-induced apoptosis
what is equilibrium?
Some cancer cells evade complete destruction but are kept in check by immune pressure.
Mutations accumulate, selecting for immune-resistant variants.
Key players: CD8+ T cells, CD4+ Th1 cells, IFN-γ.
what is escape?
Tumour cells develop mechanisms to evade immune detection.
Strategies include:
Downregulating MHC-I (to avoid T cell recognition).
Upregulating PD-L1 (to suppress T cells).
Recruiting immunosuppressive cells (Tregs, M2 macrophages).
How does PD-1/PD-L1 blockade work in cancer therapy?
1️⃣ Normal PD-1 Function:
PD-1 (on T cells) binds PD-L1 (on tumour cells) to suppress T cell activation, preventing excessive immune responses.
2️⃣ Tumour Immune Evasion:
Cancer cells overexpress PD-L1, turning off T cells to escape immune attack.
3️⃣ Checkpoint Inhibitor Action:
Anti-PD-1 (e.g., Nivolumab, Pembrolizumab) or Anti-PD-L1 (e.g., Atezolizumab) antibodies block this interaction.
T cells remain active, allowing them to attack tumour cells.
4️⃣ Clinical Outcomes:
Effective in cancers like melanoma, lung cancer, and bladder cancer.
Potential immune-related side effects (autoimmunity, inflammation).
🔹 What are the steps in CAR-T cell therapy?
1️⃣ Leukapheresis:
Patient’s T cells are collected from the blood.
2️⃣ Genetic Engineering:
A Chimeric Antigen Receptor (CAR) gene is inserted into the T cells using a viral vector.
The CAR includes:
An antigen-recognition domain (targets tumour antigen, e.g., CD19).
A costimulatory domain (e.g., CD28, 4-1BB) for enhanced activation.
A signalling domain (CD3ζ) to trigger T cell killing.
3️⃣ Expansion:
Modified T cells are expanded in the lab to increase their numbers.
4️⃣ Preconditioning Chemotherapy:
Patient receives lymphodepleting chemotherapy to make space for CAR-T cells and enhance their efficacy.
5️⃣ Infusion of CAR-T Cells:
Engineered CAR-T cells are infused back into the patient.
6️⃣ Tumour Targeting & Killing:
CAR-T cells bind tumour antigens, activate, and release perforin/granzyme to kill cancer cells.
7️⃣ Monitoring & Management:
Patients are observed for side effects like Cytokine Release Syndrome (CRS) and Neurotoxicity (ICANS).
🔹 How does the tumour microenvironment suppress immune responses?
1️⃣ Hypoxia & Metabolic Changes:
Tumour cells increase glycolysis (Warburg effect), consuming glucose and producing lactate, which suppresses T cell function.
2️⃣ Secretion of Immunosuppressive Cytokines:
Tumours release TGF-β, IL-10, and VEGF, which inhibit T cells and promote tumour growth.
3️⃣ Recruitment of Immunosuppressive Cells:
Tumours attract:
Regulatory T cells (Tregs) – Suppress cytotoxic T cells.
M2 Macrophages – Promote tissue repair instead of tumour destruction.
Myeloid-Derived Suppressor Cells (MDSCs) – Block T cell responses.
4️⃣ Expression of Immune Checkpoints:
Tumour cells overexpress PD-L1, inhibiting T cell activation.
5️⃣ Formation of a Physical Barrier:
Dense fibrotic stroma prevents immune cells from infiltrating solid tumours.
🔹 How does p53 prevent cancer?
1️⃣ DNA Damage Sensing:
When DNA is damaged, sensors (e.g., ATM/ATR kinases) activate p53.
2️⃣ Cell Cycle Arrest:
p53 upregulates p21, a CDK inhibitor that halts the cell cycle at G1/S.
3️⃣ DNA Repair:
If damage is repairable, p53 activates DNA repair genes (e.g., BRCA1).
4️⃣ Apoptosis (if damage is severe):
p53 induces BAX/PUMA, triggering mitochondrial apoptosis.
5️⃣ Senescence:
If apoptosis is avoided, p53 drives the cell into permanent cell cycle arrest (senescence).
🔹 How do cancers evade p53?
Mutations in TP53 (gene coding for p53) prevent it from functioning.
Overexpression of MDM2, a negative regulator that degrades p53.
Inactivation of upstream DNA damage sensors (ATM/ATR).
How can p53 be reactivated in cancer therapy?
MDM2 inhibitors (e.g., Nutlin-3) prevent p53 degradation.
Gene therapy (e.g., restoring wild-type p53 using adenoviruses).
How do tumour-specific neoantigens trigger an immune response?
1️⃣ Generation of Neoantigens
Tumour cells acquire mutations that create new, abnormal proteins.
These neoantigens are not found in normal cells.
2️⃣ Antigen Processing
Neoantigens are processed by the proteasome into small peptide fragments.
3️⃣ Antigen Presentation
Peptides are transported to the endoplasmic reticulum (ER) via TAP transporters.
They bind to MHC-I molecules, which are transported to the cell surface.
4️⃣ Recognition by CD8+ T Cells
Cytotoxic T cells (CTLs) use their T cell receptors (TCRs) to recognise neoantigen-MHC complexes.
5️⃣ T Cell Activation
If the TCR binds the neoantigen strongly, the T cell receives a primary signal.
Co-stimulation (CD28-B7 interaction) provides a secondary signal.
Cytokines (e.g., IL-2) drive T cell proliferation.
6️⃣ Tumour Cell Killing
Activated CD8+ T cells release perforin and granzymes, inducing apoptosis.
🔹 Immune Evasion Mechanisms:
Tumours can downregulate MHC-I, hiding from T cells.
They may secrete immunosuppressive cytokines like IL-10.
How does the JAK-STAT pathway regulate immune responses and cancer growth?
1️⃣ Cytokine Binding to Receptor
Cytokines (e.g., IFN-γ, IL-6) bind to their receptors on immune cells.
2️⃣ JAK Activation
Receptors recruit and activate Janus kinases (JAKs), leading to phosphorylation.
3️⃣ STAT Activation & Dimerisation
Signal transducer and activator of transcription (STAT) proteins are phosphorylated.
They dimerise and translocate to the nucleus.
4️⃣ Gene Transcription
STAT dimers bind DNA and promote gene expression related to immune responses, inflammation, and cell survival.
JAK-STAT in Cancer
Mutations in JAK2 → Uncontrolled STAT activation, leading to leukaemias and myeloproliferative neoplasms (MPNs).
Excessive IL-6/JAK-STAT signalling → Tumour growth and resistance to apoptosis.
Targeting JAK-STAT in Therapy
JAK inhibitors (e.g., Ruxolitinib) are used for MPNs.
Blocking IL-6/JAK-STAT helps reduce cancer-associated inflammation.
How do tumours promote blood vessel formation?
1️⃣ Hypoxia Triggers Angiogenesis
Large tumours experience hypoxia due to limited oxygen supply.
Hypoxia stabilises HIF-1α, a key transcription factor.
2️⃣ VEGF Secretion
HIF-1α induces the release of vascular endothelial growth factor (VEGF).
3️⃣ Endothelial Cell Activation
VEGF binds VEGFR on endothelial cells, triggering proliferation.
MMPs (matrix metalloproteinases) degrade the extracellular matrix, allowing vessel formation.
4️⃣ New Blood Vessel Formation
Tip cells extend filopodia to guide vessel growth.
Stalk cells form the vascular structure.
5️⃣ Tumour Vascularisation
New vessels supply the tumour with oxygen and nutrients.
This enables metastasis, as tumour cells enter the bloodstream.
Anti-Angiogenic Therapy
Bevacizumab (anti-VEGF antibody) blocks angiogenesis.
VEGFR inhibitors (e.g., Sorafenib) prevent endothelial cell activation.
How do cancer cells spread via the epithelial-to-mesenchymal transition (EMT)?
1️⃣ Epithelial Cell Features (Pre-EMT)
Cell-cell adhesion (E-cadherin maintains tight junctions).
Stationary nature (cells remain in tissue).
2️⃣ EMT Induction
Tumour cells receive signals (e.g., TGF-β, Wnt, Notch) from the microenvironment.
3️⃣ Loss of Adhesion & Polarity
E-cadherin downregulation → Cells detach from neighbours.
Cytoskeletal changes → Increased motility.
4️⃣ Invasion & Intravasation
Tumour cells penetrate the basement membrane and enter blood vessels.
5️⃣ Circulation & Survival
Cancer cells travel in the bloodstream as circulating tumour cells (CTCs).
Platelet cloaking protects them from immune attack.
6️⃣ Extravasation & MET
Cancer cells exit blood vessels and revert to an epithelial-like state (MET).
They establish secondary tumours (metastases) in new tissues.
🔹 Targeting EMT-MET in Therapy
TGF-β inhibitors prevent EMT-driven metastasis.
Integrin blockers reduce tumour cell adhesion.
🔹 How do cancer cells alter metabolism to fuel growth?
1️⃣ Switch to Aerobic Glycolysis
Even in oxygen-rich conditions, cancer cells prefer glycolysis over oxidative phosphorylation.
This produces lactate, leading to acidosis.
2️⃣ Increased Glucose Uptake
Cancer cells upregulate GLUT1 transporters to take in more glucose.
3️⃣ Mitochondrial Reprogramming
Reduced oxidative phosphorylation to avoid ROS accumulation.
Use of glutamine for biosynthesis (glutaminolysis).
4️⃣ Lactate Export & Microenvironment Modulation
Excess lactate is exported via MCT4 transporters.
Acidic conditions promote invasion and immune evasion.
5️⃣ Biosynthesis for Proliferation
Glycolysis intermediates feed into nucleotide, amino acid, and lipid synthesis to support rapid division.
Therapeutic Targeting of Cancer Metabolism
GLUT1 inhibitors reduce glucose supply (e.g., Fasentin).
LDH inhibitors block lactate production (e.g., FX11).
Metformin inhibits mitochondrial complex I, affecting energy production.
