LECTURE 12 (Cancer) Flashcards
What are the characteristics of tumour cells?
- Growth signal self-sufficiency
- Ability to evade apoptosis
- Insensitivity to antigrowth signals
- Unlimited replicative potential
- Sustained angiogenesis
- Tissue invasion and metastasis
What do the malignant phenotype of cancers result from?
- defective regulation of cell proliferation
- resistance of tumour cells to apoptotic death
- ability of tumour cells to invade host tissues + metastasise to distant sites
Which cells are mostly involved in immune responses against tumours?
- CD8+ cytotoxic T lymphocytes
- CD4+ Th1 cells (T helper cells)
What do immune responses usually exhibit?
The defining characteristics of adaptive immunity
- specificity
- memory
ADDITIONAL INFO:
immunodeficient humans are at increased risk of developing tumours (mainly increased susceptibility to virus infection)
What is the majority of tumour antigens that elicit protective immune responses?
“Neoantigens” produced by mutated genes in different tumour cell clones
What happens in virus-induced tumours?
Tumour antigens are mostly foreign proteins produced by oncogenic viruses + the immune response seen is an antiviral response
EXPLANATION:
since antigens are not produced by healthy cells + no normally present -> immune system is not tolerant to them
Describe Neoantigens
- Products of randomly mutated genes “passenger mutations” (reflects genetic instability of cancer cells) + products of mutated oncogenes/tumour suppressor genes “driver mutations” (involved in oncogenesis)
- Generate new MHC-binding peptides + presented on MHC I presented to T cells
- Often cytosolic or nuclear proteins degraded by proteasomes
- The same type of tumour in different patients may express different sets of neoantigens -> “clonal neoantigens”
What are tumour antigens products of?
- Genes that are silenced in normal cells and depressed/activated in tumour cells
- Proteins made by normal cells but produced in excessive amounts by tumours
What are the major categories of unmutated tumour antigens that are more abundant in tumours than normal tissues?
- Cancer-testis antigens
- Proteins encoded by amplified genes
- Tissue differentiation antigens
What are Cancer-testis antigens?
Proteins expressed in gametes and trophoblasts and in many types of cancers but not in normal somatic tissue-proteins
Describe antigens of Oncogenic viruses
- Products of oncogenic viruses function as tumour antigens and elicit specific T cell responses that may serve to eradicate virus induced tumours
- Processed + presented on tumour cell surface
- Examples: EBV lymphomas + HPV associated cancers -> arise more frequently in immunosuppressed individuals
What are Oncofoetal antigens?
Proteins thought to be expressed at high levels in cancer cells and in foetal but not in adult tissues
Two most studied oncofoetal antigens are CARCINOEMBRYONIC ANTIGEN (CEA) and A-FETOPROTEIN (AFP)
What is Carcinoembryonic antigen (CEA)?
- highly glycosylated membrane protein that functions as an intercellular adhesion molecule
- high CEA expression is restricted to cells in gut, pancreas and liver during the first two trimesters
What is a-fetoprotein (AFP)?
- a circulating glycoprotein normally synthesised + secreted in foetal life by the yolk sac and liver
- elevation of serum levels in patients with hepatocellular carcinoma, germ cell tumours and gastric and pancreatic cancers
What is the principal mechanism of immune protection against tumours?
Killing of tumour cells by CD8+ cytotoxic T cells
EXPLANATION: CTLs recognise + kill potentially malignant cells that express peptides derived from tumour antigens presented with MHC I MOLECULES
What induces CTL responses?
Recognition of tumour antigens on host antigen-presenting cells (APCs)
EXPLANATION: APCs ingest tumour cells or their antigens and present the antigens to T cells -> tumours display class I MHC-associated peptides “CROSS-PRESENTATION” or “CROSS-PRIMING”
What does the activation of naive CD8+ T cells to proliferate and differentiate into active CTLs require?
- Recognition of antigen (class I MHC-associated peptide)
- Co-stimulation and/or help from class II MHC-restricted CD4+ T cells
How do antibodies kill tumour cells?
- Activation of complement
- Antibody-dependent cell-mediated cytotoxicity
[Fc receptor-bearing macrophages or natural killer (NK) cells mediate the killing]
How do tumour cells become susceptible to killing by NK cells?
- Down-regulate expression of class I MHC
[down-regulation makes tumours good targets for NK cells] - Upregulate expression of ligands that bind activating NK cell receptors
[tumours express ligands for NKGD2 activating receptor on NK cells (e.g MIC-A, MIC-B) -> NKGD2 can override inhibitory signals from class I MHC binding receptors)
Which cytokines increase the tumorcidal capacity of NK cells?
- IL-2
- IL-15
- IL-12
Macrophages are capable of both inhibiting and promoting the growth and spread of cancers, depending on their activation state (TRUE/FALSE)
TRUE
What are the different ways macrophages are activated?
- Recognition of damage-associated molecular patterns from dying tumour cells by macrophage innate immune receptors
- IFN-gamma produced by tumour specific T helper cells or CTLs
