8 tumours, immunosurveillance Flashcards

Question

Give an example of a checkpoint inhibitor.

Answer 1

Ipilimumab (anti-CTLA-4) → enhances T cell activation.

Answer 2

Prevents tumours from suppressing T cells, allowing them to attack cancer cells.

Answer 3

To stimulate tumour-specific immune responses after cancer diagnosis.

Answer 4

A therapeutic vaccine for prostate cancer using recombinant vaccinia expressing PSA.

Answer 5

Phase II: Increased median survival by 8.5 months. Phase III: Results were disappointing; now tested with checkpoint inhibitors.

Answer 6

An autologous dendritic cell-based therapy for prostate cancer.

Answer 7

High cost ($100,000 per patient) for a modest survival benefit (4.1 months).

Answer 8

Chimeric Antigen Receptor T cell therapy.

Answer 9

T cells are engineered to express a receptor targeting a specific tumour antigen and reinfused into the patient.

Answer 10

Highly specific tumour targeting. Not restricted by MHC alleles.

Answer 11

Potential for severe immune-related side effects like cytokine release syndrome (CRS).

Answer 12

Acute lymphoblastic leukaemia (ALL). Non-Hodgkin lymphoma. Chronic lymphocytic leukaemia.

Answer 13

Antibodies conjugated with toxins/radioisotopes that specifically kill tumour cells

Answer 14

Poor tumour penetration. Binding to normal cells with the same antigen. Circulating antigen ‘mopping up’ antibodies.

Answer 15

Tumour antigen variability. Immune tolerance to self-antigens. Tumour immune evasion mechanisms.

Answer 16

Knockout mice lacking key immune components (e.g., IFN-γ, perforin, or NK cells) develop tumours at a higher rate than normal mice.

Answer 17

Higher levels of TILs in a tumour correlate with better patient prognosis, suggesting the immune system actively fights tumours.

Answer 18

PD-1 (on T cells) binds PD-L1 (on tumour cells) to suppress immune responses, allowing tumours to evade detection.

Answer 19

Nivolumab and Pembrolizumab (anti-PD-1) Atezolizumab and Durvalumab (anti-PD-L1)

Answer 20

They block PD-1/PD-L1 interactions, restoring T cell activity against tumours.

Answer 21

Engineered antibodies that bind both T cells (via CD3) and tumour cells (via tumour-specific antigen) to promote targeted killing.

Answer 22

They encode tumour-specific antigens, prompting the immune system to recognize and destroy cancer cells.

Answer 23

NK cells can kill cancer cells without prior sensitization. CAR-NK therapies are being developed as an alternative to CAR-T cells.

Answer 24

The ecosystem around a tumour, including immune cells, fibroblasts, blood vessels, and extracellular matrix.

Answer 25

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

Answer 26

Cancer cells preferentially use aerobic glycolysis (even in oxygen-rich conditions) to generate energy, supporting rapid proliferation.

Answer 27

1. Cytokine Release Syndrome (CRS): Overproduction of inflammatory cytokines, leading to fever, hypotension, and organ dysfunction. 2. Immune Effector Cell-Associated Neurotoxicity Syndrome (ICANS): Neurological side effects, including confusion, seizures, and coma.

Answer 28

Solid tumours have dense stroma, making it hard for CAR-T cells to infiltrate. The tumour microenvironment suppresses T cell function.

Answer 29

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).

Answer 30

Elimination (Immunosurveillance) Equilibrium (Tumour Dormancy) Escape (Tumour Progression)

Answer 31

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

Answer 32

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.

Answer 33

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).

Answer 34

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).

Answer 35

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).

Answer 36

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.

Answer 37

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).

Answer 38

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).

Answer 39

MDM2 inhibitors (e.g., Nutlin-3) prevent p53 degradation. Gene therapy (e.g., restoring wild-type p53 using adenoviruses).

Answer 40

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.

Answer 41

Tumours can downregulate MHC-I, hiding from T cells. They may secrete immunosuppressive cytokines like IL-10.

Answer 42

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.

Answer 43

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.

Answer 44

JAK inhibitors (e.g., Ruxolitinib) are used for MPNs. Blocking IL-6/JAK-STAT helps reduce cancer-associated inflammation.

Answer 45

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.

Answer 46

Bevacizumab (anti-VEGF antibody) blocks angiogenesis. VEGFR inhibitors (e.g., Sorafenib) prevent endothelial cell activation.

Answer 47

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.

Answer 48

TGF-β inhibitors prevent EMT-driven metastasis. Integrin blockers reduce tumour cell adhesion.

Answer 49

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.

Answer 50

GLUT1 inhibitors reduce glucose supply (e.g., Fasentin). LDH inhibitors block lactate production (e.g., FX11). Metformin inhibits mitochondrial complex I, affecting energy production.