cancer - block d Flashcards
Cancer stats
Breast cancer is the most common cancer in the UK
Lung, breast, colorectal, and prostate account for over 1/2 of new cases
Most significant contributing risk factor for most cancers is older age
Immunologists can find cures or preventative measures
Cancer
A disease caused by the uncontrolled reputation of a cell
Oncogenic mutations in cell result in activating the cell cycle and/or inhibiting the normal process that result in cell removal e.g. apoptosis
Pathogenesis of 15–20% of human tumours is linked to Infection-driven inflammation
Infection-driven inflammation
Human papillomavirus (HPV) is involved in cause of cervical intraepithelial neoplasia (CIN) and cervical, penile, vaginal, vulvar, anal cancers
Integration of HPV DNA into the genome of the infected cell leads to the deletion of host genes e.g. E2 - a negative regulator of the HPV oncogenes E6 and E7 – promotes a malignant change in the host cell
Chronic inflammation in cancer
Chronic inflammation caused by cigarette smoking – causes an imbalance in cytokine secretion and inflammatory responses:
Favours transformation of normal epithelial cells into malignant cells
Cancer result in lung cancer
Vaping may be related to increase risk of mouth cancer
Pathways to cancer
Intrinsic pathway to cancer:
series of genetic events (e.g. activation of oncogenes, inactivation of tumour suppressor genes) causing neoplastic transformation e.g. breast cancer
Extrinsic pathway to cancer:
inflammatory leukocytes (white blood cell) and soluble mediators maintain inflammation at a site and increase cancer risk e.g. colon, prostate, pancreas
Cells form a mass – called a tumour
Cancer cells remain localised or spread (metastatic)
Role of immune cells in cancer
Initial immune response - innate cell i.e. macrophages, myeloid-derived suppressor cells, mast cells, eosinophils and neutrophils
Their activation contributes to reinforce the pro-inflammatory milieu
Tumors escape from immunosurveillance occurs through different mechanisms e.g. cancer cells present different antigens (e.g. PD-L1/CTLA-4) or cancer suppresses T cell responses (via Tregs).
Cytotoxicity of body’s own cells depends on induction of apoptosis:
Innate response: NK cells
Specific immune response: Cytotoxic T cells – usually CD8+ T cells
What immune cells can destroy cells in your own body
Innate : NK cells, macrophages
Specific : T cells
NK cell mediated killing of cancer cells
Killing of target cancer cell by NK cell depends on activation/inhibition signals
MHC Class I molecule expression on target cell inhibits NK cell activation
Release of granzymes/perforin into target cell via immunological synapse
Cancer cells dies by apoptosis
T-cell Mediated Killing of Cancer Cells
Killing of target cancer cell depends on recognition of ‘foreign antigen’ on cancer cell by T cell receptor
Difficulty is identifying cancer-specific antigens
Role of t helper and cytotoxic t cells
Both CD4+ T helper cells (TH) and CD8+ cytotoxic cells (Tc) can be involved in the cytotoxic response against cancer cells
Cytokines produced by TH cells can:
Increase production of (Tc) cells directly by cytokines they produce (IFNg)
Act on dendritic cells: improve antigen presentation
Antibody-mediated immunity
Carry out antibody-directed/dependent cellular cytotoxicity (ADCC)
Clinically use antibodies to treat cancers by targeting TSA/TAAs –challenge is identifying a key antigen that is present on specific types of tumours
FDA has approved checkpoint blocking antibodies known as checkpoint inhibitors e.g. ipilimumab: CTLA-4 & nivolumab PD-1 – for better clinical outcomes
Action not defined - improved anti-tumour responses by an increase in T cell activation markers, CTL infiltration, and pro-inflammatory cytokine/chemokine production
How Do Cancer Cells Avoid Protective Immune Responses?
Cancer cells:
Do not express/low expression of MHC I/II molecules – not recognised by T cells
Express antigens which have poorly immunogenic epitopes
Release immunosuppressive cytokines - TGF-β used by tumours:
- CD4+CD25- develop into CD4+CD25+ Treg cells – switch off cytotoxic T cells
- Induce the development of Th17 type response designed to counter autoimmunity and reduce the fraction of activated TH cells
- TH2 cytokines e.g. tumour-derived IL-4 and IL-10 can block tumour-specific CTL activity
Induce T cell apoptosis
Tumour Microenvironment (TME)
Innate cells produce a TME favouring tumour proliferation & survival
Macrophages (Mφs) can be divided into different types (M1 and M2)
M2 Mφs : are anti-inflammatory protecting host tissues and produce growth factors e.g. epidermal growth factor (EGF) & vascular endothelial growth factor (VEGF)
M2 macrophages enhance tumour cell proliferation and vascularisation
M2 Mφs are present at a higher ratio in the bone marrow of AML patients compared to M1 Mφs.
T cell therapy: CAR T cells
Transfusion of autologous or allogeneic tumour-responsive T cells back into the patient’s body
CAR-T cells (chimeric antigen receptor T cells) - modified T cells not restricted by MHC molecules
Have a recombinant receptor with both tumour-antigen-binding and T cell-activating functions
1st generation: Only one intracellular signal component CD3z
2nd generation: Added one costimulatory molecule
3rd generation: Two costimulatory molecules added
4th generation: Activate the downstream transcription factor to induce cytokine production after recognition of target antigen(s)
5th generation - Gene editing to inactivate the TRAC gene – causes removal TCR alpha and beta chains (leads to enhanced potency of CAR T –cells)
Clinical efficacy of CAR T cells
Number of CAR-T cells ranges from1 x 105/kg to 1 x1010/kg
One patient with Acute lymphoblastic leukemia - cancer free for 5 years
Minimum cell number required for CAR-T cell therapy to exert its anticancer effects was only one cell
MM- incurable disease, and only 30% patients are still alive 10 years after diagnosis.
CAR-T cell therapy for 35 MM patients who relapsed or were resistant to treatment - 74% experienced a complete response after receiving BCMA CAR-T cells.
