Chapter 17 Flashcards
Oncogenesis?
Process of tumour formation
-overtime, with accumulation of mutations allowing to avoid normal growth constraints
Multi-hit model explained?
A single mutation isn’t enough to lead to cancer, need subsequent mutations in the decedents of original cell to out-live/out-grow other neighbouring cells
Cancer Promoting Mutations?
Proto-oncogenes
-Via mutations, causing gain in function to drive cell proliferation independent of growth factors, forming oncogenes
Tumour Supressor genes
-mutations, causing loss of function that removes functionality of TSG, needed both alleles to be mutated to have an effect
How does the immune system recognize Cancer?
Mutations lead to formation of neoantigens that can be recognized by T cells for cancer cell death
Mutations that can lead to neoantigen formation?
Single Nucleotide Variations (SNVs) or point mutations
Indels, in frame or frameshift
Fusion genes, involving the combination of 2 genes
Splice variants, resulting in expression of multiple variants of one gene
Tumour Specific vs Tumour associated antigens
TSAs: unique to tumour, neoantigens
TAAs: involve inappropriate expression of genes, or over expression of normal genes, NOT NEOANTIGENS
Ideal Immune Response towards tumours
Tumour antigens taken up by APC and presented to T cells for activation
T cell population proliferate, and activate B cells to create antibodies against Tumour cells while CD8 T cells head towards tumour site to eliminate tumour
2 mechanisms of tumour elimination?
Intrinsic pathway via perforin and granzyme release to undergo apoptosis
Extrinsic pathway
via FasL and Fas interaction to undergo apoptosis
Explain ADCC?
Antibody dependent cytotoxicity
-Opsonization of tumour cells resulting in activation of immune effector cells such as NK cells
through Fc-FcyR interactions
Explain ADCP?
Antibody dependent phagocytosis
–Opsonization of tumour cells allowing for Fc mediated phagocytosis
What is TIME? and its classes?
Tumour Immune Microenvironment?
3 classes categorized by the presence of immune cell infiltration to the tumour
- Hot (inflamed)
-Lots of immune response with T cells - Cold (excluded)
-Not as much immune response - Cold (ignored)
-worst case which creates physical behaviour from immune response
TILs?
Tumour infiltrating Lymphocytes
-more = higher survival rate
Tumour Immunoediting?
the process by which the composition of sub populated tumour cells changing in response to selective pressures from the immune system
Tumour Immune Evasion methods?
- Low immunogenicity = no peptide/MHC ligand, with no co-sim molecules
- Tumour treated as self antigen
- Antigenic modulation = T cells unable to eliminate tumour cell due to lost antigens
- Tumour-induced immune suppression via molecules being secreted by tumour cell to inhibit T cells
- Tumour-induced privileged site via factors secreted by tumour cell that create physically barrier for the immune system (like cold excluded)
MIC proteins?
MHC class 1 chain related proteins
-protein secreted by tumour cell that are recognized by immune cells
->induces apoptosis
Needs to be insoluble mic bound to tumour cell, not soluble
T cell regulation via PD-1/PD-L1
PD-L1 secreted by the tumour cell binds to PD-1 of the T cell, causing inhibition of T cell recognition of tumour cell
T cell regulation via CTLA-4
CTLA-4 = Cytotoxic T cell lymphocyte antigen 4
-Upregulation after activation in T cell + T regs
-outcompetes B7 binding to CD28 which down regulates the activation of T cells, further internalizing B7/removing B7 from APC surface
Like a Break for the immune system
Therapeutic Antibodies and Immune checkpoint blockades
Treatment with therapeutic antibodies targets checkpoints in the immune regulatory processes of CTLA-4 and PD-1/PD-L1
Inhibiting function of checkpoints allows for persistent immune response to occur
ACT?
Adoptive Cell Transfer
-Tumour specific T cells can be expanded in vitro and selected based on neoantigen specificity
-Done via excising tumour, expanding population of TILs specific for patient’s tumour antigens
-Reinfuse Tumour specific T cells back into the patient
Explain Targeted radiopharmaceutical therapy?
Tag radioactive isotope to antibody against tumour antigen
-Once bound to tumour, cancer cells including those healthy surrounding begin to die due to radiation damaging DNA
-Not the best therapy due to killing both healthy and unhealthy cells
