Cancer Immunology Flashcards
What is cancer? (1)
Hyper proliferation of cells
What is metastasis? (2)
Cells in tumour mass acquire capabilities in order to change morphology and move throughout body
What are oncogenes? (3)
Drive abnormal cell proliferation
As a consequence of genetic alterations that either increase gene expression or lead to uncontrolled activity of the oncogene regulation or oncogene encoded proteins
What are tumour suppressor genes? (3)
Under normal conditions they act to inhibit cell proliferation and tumour development
In many tumors, these genes are lost or inactivated, if you remove these negative regulators of cell proliferation they contribute to the abnormal proliferation of tumour cells
Genes whose normal function is control and inhibit cellular replication.
What is the two-hit hypothesis? (3)
Most tumor suppressor genes require both alleles to be inactivated, either through mutations or through epigenetic silencing, to cause a phenotypic change
What are the hallmarks of cancer devised by Douglas Hanahan and Robert Weinberg? (1)
Comprises six biological capabilities acquired during the multistep progress to cancer
Describe the 6 hallmarks of cancer (6)
Self-sufficiency in growth signals
Insensitivity to antigrowth signals
Evading apoptosis
Tissue invasion and metastasis
Limitless replicative potential
Sustained angiogenesis
What is tumour heterogeneity? (2)
Tumours are more than insular masses of proliferating cancer cells
Instead, they are complex tissues composed of multiple distinct cell types that participate in heterotypic interactions with one another
What are cold tumours? (3)
Exclusion of CD8+ T cells and NK cells from the tumour
Immunosuppressive immune cells in tumour
Poor prognosis and response to immunotherapy
What are hot tumours? (3)
CD8+ T cells and NK cells are present in the tumour
Suppression of immunosuppressive cell types
Improved prognosis and killing of tumour cells with immunotherapy treatment
What are the immunological problems with cancers? (2)
Tumour are self cells
Contain self proteins, whichif recognisedby the immune system would result in autoimmune disease
What are the red flags the immune system recognises? (3)
Integrated stress response - Increased replicationresults in transcription and translation of proteins and macromolecules at a faster rate than normal. A lot of incorrect folding and general mechanisms of a normal cell being done poorly
Increased replication results in the use of a lot of nutrients. Anaerobic and aerobic processes that are normally carefully regulated are altered resulting in different amounts of waste products
Increased replication results in cellular stress - Recognition of Stressed induced ligands
How are tumour cells able to hide from the immune system? (2)
By reducing the expression of MHC class I on their surface
No MHC class I means tumour specific T cells activity is reduced because your T cells cant recognize whether you are non self or not
How can natural killer cells recognise tumour cells? (2)
Recognise:
- reduced MHC class I
- stress induced ligand on surface
This induces activation of NK cells
What are NK cells? (1)
Cells that have evolved to recognise and kill targets without self MHC class I and with stress induced ligand
What is the aim of the immune system in the tumour microenvironment? (1)
Recognition of unregulated growth
What is the role of Damage Associated Molecular patterns (DAMPs) in the tumour microenvironment? (2)
Recognition of tumor - derived DAMPs usually initiates the activation of inflammatory signalling cascades to activate immune cells
Can also lead to sterile inflammation that can form a reinforcing loop of tumorigenesis.
What is the integrated stress response? (2)
Evolutionarily conserved intracellular signaling network
ISR aims to return of homeostasis or induce cell death
Describe the integrated stress response (3)
Activates the eukaryotic translation initiation factor eIF2
Triggers the translation of the key activating transcription factor ATF4 which is a multifunctional transcription regulatory protein that participates in a variety of cellular responses to different stresses or intercellular signaling molecules
Role of Transforming Growth Factor-beta in the tumour microenvironment (3)
Pleotropic inhibitory cytokine
Signals via SMAD dependent and independent pathways to transcription factors that functionally inhibit immune cell function
Role of Cyclo-oxygenase2 / Prostaglandin-E2
Inflammatory mediators in the tumour microenvironment (3)
Inflammatory mediators
Derived from Arachidonic Acid
Involved in homeostatic resolution of immune responses.
Role of Indoleamine 2, 3-Dioxygenase in the tumour microenvironment (2)
Function is to degrade tryptophan
W degradation products have immuno-inhibitory effects
Name the different immunomodulatory molecules in the gut (3)
Transforming growth factor beta
Retinoic acid
Interleukin 10
Describe the role of transforming growth factor beta in the gut (4)
An inhibitory cytokine
Produced as an inactive pro-form and held inactive as a latent form
Integrins expressed in the gut epithelium, activate TGFbeta and induce regulatory T cell differentiation
TGFb in the intestines induce expression of CD8aa and CD103. CD8aa can down modulate TCR signaling so prevent over activity in the gut
Describe the role of retinoic acid in the gut (3)
Produced by epithelial cells
Retinol the substrate for RA must be absorbed by from the diet
Retinol is stored in the liver and delivered to the intestines for local production of RA or the generation of Tregs
Describe the role of Interleukin 10 in the gut (4)
An immunomodulatory cytokine
Signaling contributes to downregulation of TLR signalling MYD88, TRIF, TRAF6, CD14, and NFkB signalling inhibitors
Derived from Tregs
Deletion of IL10 in Tregs induces colitis.
How are macrophages differentiated? (1)
By TGFb
Describe the differences between M1 and M2 macrophages (9)
M1:
Pro-inflammatory
Anti-tumoral
Tissue-specific antigen presentation
Tissue injury
M2:
Anti-inflammatory
Pro-tumoral
Wound healing
Parasite clearance
Immunosuppression
Role of tumour infiltrating lymphocytes in cancer (1)
Often a marker of good prognosis
suggesting role in controlling cancer
Describe chimeric antigen receptor T cell therapy (5)
Acquire T cells from blood
Create CAR T cells
Grow many CAR T cells
Infuse CAR T cells into patients
CAR T cells attack cancer cells
Problems with CAR T cell therapy (3)
Access to tumour microenvironment is restricted - immunosuppressive and nutrient-restricted tumour microenvironment
Tumour heterogeneity and antigen escape
CAR T cell trafficking and infiltration
How can cancers occur (4)
Single point mutation in genes which can impact proliferation and change its function
Deletion in sections of genes
DNA damage - agent disrupts DNA at particular site important for cell proliferation
Genes spliced together
What is Rb? (3)
P53 stops tumours from developing by:
1. In response to DNA damage and stress it will halt cell cycle
2. Inducing apoptosis
Mutations in these genes are common in lots of different cancers.
What is P53? (3)
P53 stops tumours from developing by:
1. In response to DNA damage and stress it will halt cell cycle
2. Inducing apoptosis
What is MYC? (5)
Oncogene
Tightly controls cell cycle state
Binds particular targets with high or low affinity at different places in cell cycle
Regulates the way cell moves through cell cycle
Myc work not working properly - keep driving proliferation
What cells can be found in tumour microenvironment and what is important about them? (6)
Have a different functional output as they are altered by the tumour
Activating molecules
Dendritic cells
B/T/NK cells
Neutrophils
Macrophages etc
What causes immune inhibition in the TME (2)
Transforming Growth Factor-beta
Cyclo-oxygenase 2 / Prostaglandin-E2
Indoleamine 2, 3-Dioxygenase
Antibody targeting of tumour cells (1)
Bi-specific antibody
How can we exploit the anti-tumour activity of the Immune system to
treat cancer? (3)
Inhibiting immune checkpoints with antibodies
T cell targeting of tumour cells
Antibody targeting of tumour cells
