Immune surveilance

Question 1

how are cancer cells different from normal cells?

Answer 1

• rapid uncontrolled growth
• increase mobility
• invade tissue
• evade immune system
• metastasise

Question 2

what can immunodeficieny lead to?

Answer 2

tumor formation; kaposi sarcoma, lymphoma

Question 3

what can inflammatory conditions lead to?

Answer 3

cancers; ulcerative colitis and colon cancer

Question 4

what was research into how the body can defend against cancer?

Answer 4

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

Question 5

adaptive immune response

Answer 5

involves specialised immune cells and antibodies that attack and destroy foreign invaders and retain memory antigens

Question 6

what are the immune system’s 3 major ways of preventing tumors

Answer 6

• speedy resolution of inflammation
• elimination of viral infections
• early elimination of tumor cells before they can do harm

Question 7

what is tumor immunosurveillance?

Answer 7

process by which immune system, e.g. lymphocytes, continually recognise cancerous and pre-cancerous cells = to their elimination before they can cause damage

Question 8

tumorigenesis

Answer 8

• normal cells undergoing change
• develop abnormal tumor antigens
• danger signals such as extra cellular matrix products

Question 9

immunoediting; elimination

Answer 9

• 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

Question 10

immunoediting; equilibrium

Answer 10

• 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’

Question 11

what are some features of tumor stem cells?

Answer 11

• 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

Question 12

immunoediting; escape

Answer 12

immune system unable to control tumor growth = tumor progression

Question 13

what do some tumor cells express?

Answer 13

• MHC class I/peptide complexes
• ligands to CD8+ T cells = activation and destruction of the tumor cell

Question 13

how are CD4+ t cells activated?

Answer 13

APCs take up cell debris from tumor cells
- pinocytosis
- receptor mediated endocytosis

Question 14

how do activated CD4+ T cell exert antu tumor properties?

Answer 14

• 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.

Question 15

process to present on MHC

Answer 15

TH1 cytokines:
IL2 > CTL proliferation
IFNy, TNF > MHC I increase on tumor to enhance kill

Question 16

what are tumor antigens?

Answer 16

• produced by tumor cells & can trigger immune response
• important in tumor identification and targeting in immunotherapy

Question 17

tumor specific antigens

Answer 17

produced only by tumor cells

Question 18

tumor associated antigens

Answer 18

produced by tumor cells but also produced by normal cells

Question 19

TSA

Answer 19

• proteins of genes not directly involved in forming the tumor
• proteins of altered genes involved in transformation oncogenes; RAS, p53, chromosome translocation

Question 20

TAA

Answer 20

• products of overexpressed genes
• altered membrane glycolipid and glycoproteins

Question 21

tumor antigens

Answer 21

products of oncogenic viruses
viral peptides foreign > tumors immunogenic > CTLs
tumors more common with immunosupression

Question 22

Oncofoetal antigens

Answer 22

• VERY high in normal foetus on tumor cells
• de-repression on malignant transformation
• released into serum
• markers for diagnosis and following therapy

Question 23

Oncofetal antigen: carcinoembryonic Ag (CEA)

Answer 23

• highly glycosylated, Ig superfamily member
• intracellular adhesion molecule for tumor cells
• high in colorectal carcinomas

Question 24

Oncofetal antigen: Alpha-foetoprotein (AFP)

Answer 24

from liver of foetus, high in liver cancer (also in germ cell tumors, liver cirrhosis)

Question 25

defects in antigen presentation

Answer 25

- 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

Question 26

what other defects are seen in antigen presenting

Answer 26

- loss of functional b2 micro-globulin expression - loss of MHC class I alleles

Question 27

what are 3 down modulation molecules involved in antigen processing and presentation?

Answer 27

- TAP 1/2 - LMP 2/2 - tapasin

Question 28

what does lack of co-stimulation cause?

Answer 28

- 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

Question 29

what are immunosuppressive factors that are expressed/secreted by malignant cells or those surrounding cells within the stroma?

Answer 29

- 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

Question 29

what are T-regulatory cells?

Answer 29

- earlier known as T-suppressors - CD4+ Tcells with high expression of CD25 (a chain of IL-2 receptor)

Question 30

two types of T-regulatory cells

Answer 30

- nTregs; Tregs developing in the thymus to ensure tolerance to self antigens - adaptable Tregs; naive CD4+ Tcells induced in the periphery

Question 31

how are T-regulatory cells identified?

Answer 31

- by FOXP3; winged helical TF - vital for development and funciton of these cells as mutations lead to severe autoimmune condition

Question 32

what is the importance of Tregs?

Answer 32

- 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

Question 33

what is function of Treg?

Answer 33

- 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

Question 33

targeting Tregs

Answer 33

- anti CTLA-4; ipilimumab, tremelimumab - targeting CD25; LMB-2 fusion protein, Ontak

Question 34

targeting Tregs II

Answer 34

- 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

Question 35

other immunoregulatory cells

Answer 35

- 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

Question 36

takeaway on immunosurveillance

Answer 36

- immune system and tumor biology very closely intertwined - immune surveillance ongoing but imperfect - immunoediting critical in immune escape - multiple methods of immune evasion