Immune surveilance Flashcards
how are cancer cells different from normal cells?
- rapid uncontrolled growth
- increase mobility
- invade tissue
- evade immune system
- metastasise
what can immunodeficieny lead to?
tumor formation; kaposi sarcoma, lymphoma
what can inflammatory conditions lead to?
cancers; ulcerative colitis and colon cancer
what was research into how the body can defend against cancer?
skin sarcomas in mice induced by chemical carcinogen (methylcholanthrene) showed that:
- anti tumor immune response by CD8+
- production of immune memory
- specificity of individual tumors
= presence of tumor antigens
adaptive immune response
involves specialised immune cells and antibodies that attack and destroy foreign invaders and retain memory antigens
what are the immune system’s 3 major ways of preventing tumors
- speedy resolution of inflammation
- elimination of viral infections
- early elimination of tumor cells before they can do harm
what is tumor immunosurveillance?
process by which immune system, e.g. lymphocytes, continually recognise cancerous and pre-cancerous cells = to their elimination before they can cause damage
tumorigenesis
- normal cells undergoing change
- develop abnormal tumor antigens
- danger signals such as extra cellular matrix products
immunoediting; elimination
- NK, NKTs, Macs and DCs (innate)
- INFy & chemokines = tumor death
- tumor specific DCs activate adaptive immunity in draining lymph nodes
- tumor specific CD4+ and CD8+ T cells join
immunoediting; equilibrium
- elimination phase is incomplete
- tumor cells lie dormant and may modulate tumor antigen expression and stress signals
- immune system eliminates susceptible tumor clones when possible sufficient to prevent tumor expansion
- tumor heterogeneity resulting in ‘Darwinian selection’
what are some features of tumor stem cells?
- can evade host immune surveillance
- tumor seeds
- lose MHC class1 and have no NK activating ligands and silence TAA. May als downregulate b2m
- can produce immunosuppressive cytokines
- selectively recruit ‘reglatory cells’
- resistant to innate and adaptive immune response
immunoediting; escape
immune system unable to control tumor growth = tumor progression
what do some tumor cells express?
- MHC class I/peptide complexes
- ligands to CD8+ T cells = activation and destruction of the tumor cell
how are CD4+ t cells activated?
APCs take up cell debris from tumor cells
- pinocytosis
- receptor mediated endocytosis
how do activated CD4+ T cell exert antu tumor properties?
- lymphotaxin secretion resulting in direct tumor cell death
- secretion of cytotoxins activating other cells such as; NK, macrophages, CD8+ T cells
- rarely; tumors themselves can act as APCs by presenting antigens on MHC class II molecs.
Seen in some melanomas.
process to present on MHC
TH1 cytokines:
IL2 > CTL proliferation
IFNy, TNF > MHC I increase on tumor to enhance kill
what are tumor antigens?
- produced by tumor cells & can trigger immune response
- important in tumor identification and targeting in immunotherapy
tumor specific antigens
produced only by tumor cells
tumor associated antigens
produced by tumor cells but also produced by normal cells
TSA
- proteins of genes not directly involved in forming the tumor
- proteins of altered genes involved in transformation oncogenes; RAS, p53, chromosome translocation
TAA
- products of overexpressed genes
- altered membrane glycolipid and glycoproteins
tumor antigens
products of oncogenic viruses
viral peptides foreign > tumors immunogenic > CTLs
tumors more common with immunosupression
Oncofoetal antigens
- VERY high in normal foetus on tumor cells
- de-repression on malignant transformation
- released into serum
- markers for diagnosis and following therapy
Oncofetal antigen: carcinoembryonic Ag (CEA)
- highly glycosylated, Ig superfamily member
- intracellular adhesion molecule for tumor cells
- high in colorectal carcinomas
Oncofetal antigen: Alpha-foetoprotein (AFP)
from liver of foetus, high in liver cancer (also in germ cell tumors, liver cirrhosis)
defects in antigen presentation
- most healthy cells express MHC class I/ peptide complexes
- in vitro studies show that tumor cells expressing tumor antiens by this mechansm fo on to be killed by CD8+ Tcells
- tumor that has been selected not to express Class I / peptide have clear survival advantage
- epithelial tumors, especially NSCLC have very poor class I expression
what other defects are seen in antigen presenting
- loss of functional b2 micro-globulin expression
- loss of MHC class I alleles
what are 3 down modulation molecules involved in antigen processing and presentation?
- TAP 1/2
- LMP 2/2
- tapasin
what does lack of co-stimulation cause?
- melanoma cells are immunogenic but dont evoke antitumor immunity
- lack of CD80/86 expression on cell surface which is required for costimulation of T cell alongside MHC binding
- results in T cell biology and block in IL2 gene transcription
what are immunosuppressive factors that are expressed/secreted by malignant cells or those surrounding cells within the stroma?
- TGFb
- VEGF
- Prostaglandins
- IL10 ; downregulates MHC class I
- MCSF
- tumor gangliosides ; suprress anti tumor responses
- RCAS; inhibit prolif. induces apoptosis of T cells in vitro
what are T-regulatory cells?
- earlier known as T-suppressors
- CD4+ Tcells with high expression of CD25 (a chain of IL-2 receptor)
two types of T-regulatory cells
- nTregs; Tregs developing in the thymus to ensure tolerance to self antigens
- adaptable Tregs; naive CD4+ Tcells induced in the periphery
how are T-regulatory cells identified?
- by FOXP3; winged helical TF
- vital for development and funciton of these cells as mutations lead to severe autoimmune condition
what is the importance of Tregs?
- found in far greater concs, in peripheral blood in patients with variety of cancers
- found in far greater quantities within tumor milieu, ascites, draining lymph nodes in patients with cancer
what is function of Treg?
- mediate suppression on tumor specific CD4+ and CD8+ T cells via TCR
- TGFb and IL10 thought to be secreted in vivo and membrane bound in TGFb also highly potent
- research continues to reveal further modes by which Tregs mediate suppression
targeting Tregs
- anti CTLA-4; ipilimumab, tremelimumab
- targeting CD25; LMB-2 fusion protein, Ontak
targeting Tregs II
- conventional chemotherapy drugs like cyclophosphamide in smaller more frequent dosing; depletes Tregs, enhances effector T cell function
- Targeting GITR ; glucocorticoid induced tumor necrosis factor receptor ; against antibody DTA-1
other immunoregulatory cells
- myeloid derived suppressor cells; ROS and NO suppress T cell activity
- NKT cells; produce IL10 and IL4 , Th2 directing
- M2; Th2 directing APCs produce TGFb
- chemokines; tumors produce CCL2, CCL17 and CCL22 recruit Tregs
takeaway on immunosurveillance
- immune system and tumor biology very closely intertwined
- immune surveillance ongoing but imperfect
- immunoediting critical in immune escape
- multiple methods of immune evasion
