L30 Tumour Immunology

Question 1

How does the immune system discriminate self from non-self

Answer 1

Central and periperial tolerance- it makes it hard for immune system to detect cancer because they are ‘altered self’

Question 2

central tolerance

Answer 2

prevents immune system from attacking itself;
- deleted self-reactive B cells during development in bone marrow
- deletes self reactive T cells during development in thymus

Question 3

peripheral tolerance

Answer 3

induces anergy in mature B and T cells
- supresses T cells

Question 4

‘Coley’s toxins’

Answer 4

• 1893, william coley drew a link between the immune system and cancer
• spontaeous remission in cancer pateients following injection of infectious ageds, dubbed ‘coley toxins’

Question 5

Mice models that showed immune/tumor link

Answer 5

• immune deficient mice had increased susceptibiilty to tumors induced by chemical carcinagens
• another mice study showed adaptive immune response was important for tumor immunity (mice were immunized with killed tumor cells to induce a response and the immunized mice didnt grow a tumor)

Question 6

Transplant patients show immune/tumor link becuase…

Answer 6

they have higher tumor incidence and they are immune supressed typically

Question 7

presence of _____ correlates with better prognosis (showing immune/tumor link)

Answer 7

Tumor infiltrating lymphocytes (TILs) which are b and t cells

Question 8

tumor antigens recognized by T cells

Answer 8

tumor specific antigens and tumor associated antigens

Question 9

tumor specific antigens

Answer 9

• antigen different from normal sequence or responses to pathogens with an oncogenic role
• mutated oncogenic or tumor supression proteins (e.g.p 53 or MART2)
• point mutations can be bound to MHC and then stimulate an immune resoonse
• sometimes novel fusion proteins (proteins that randomly fused together that are not normal); their junction region can be recognized by the immune system as not normal

Question 10

tumor associated antigens

Answer 10

• more subtle, not mutated, but expression profile is altered. Examples:
  1. aberrantly expressed normal genes (e.g. HER2)
  2. over-expressed normal genes (e.g. ERB-B2) there present as normal, just have more expression
  3. differtation antigens (e.g. tyrosinase); undergoing cell cycle when express this, but tumors ALWAYS express this becuase they continute to divide
  4. cancer/testis antigens expressed in germ cells of testis and oveary but silent in normal somatic cells (e.g. MAGE and NY-eso-1)

Question 11

immune editing of tumors

Answer 11

selective pressure favors tumor variants that ESCAPE immune dectection

Question 12

Evasion (cancer immune escape strategy)

Answer 12

• lose expression of MHC proteins
• this means it cant PRESENT to T cells
  OR
• lose expression of antigen itself
  OR
• antigen processing machinery or ability to generate peptides that are presented by the MHC, if defects to this emerge
  OR
• IFN-y signalling can have the ability to increase tumor cell survival AND presence can drive upreg of inhibitiory factors that lead to escape
  OR
• produce decoys or soluble tumor antigen (sucha s MUC-1)

Question 13

Inhibitory immune receptors (cancer immune escape strategy)

Answer 13

• IMMUNE CHECKPOINT MOLECULES
• cancer cells upregulate expression of the ligand pdl-1, LIGAND FOR INHIBITORY RECEPTOR CALLED PD-1
• PD-1 is important in normal immune response and is upregulated on cells in order to switch them off
• IN CANCER, upregulate expression of the ligand which engages PD-1 meaning that it stays switched on
• High expression of PD-L1 by tumors predicts a poorer outcome

Question 14

PD-L1

Answer 14

• upregulated by tumors to turn off the immune checkpoint with PD-1 and continue the cell cycle
• in cancer, high PDL-1 predeicts a poorer outcome

Question 15

metabolic enzymes (cancer immune escape strategy)

Answer 15

• IDO or aginase 1 examples
• breakdown crutial amino acids that amino acids need to proliferate, so they limit them from developing

Question 16

Indoleamine dioxygenase (IDO)

Answer 16

• a metabolic enzyme that leads to tryptophan depletions and starves T cells to keep them from developing

Question 17

arginase 1

Answer 17

• a metabolic enzyme that lead to arginine depletion and starves T cells to keep them from devleoping

Question 18

regulatory T cells (cancer immune escape strategy)

Answer 18

• normal role is to dampen immune responses
• cancer cells recruit them by producing aa chemokine (CCL22) to attract them (because the T regs express the receptor)
  OR
• tumor cells produce TGF-B which promotes T-regs

Question 19

CCL22

Answer 19

• a chemokine that cancer uses to attract T-regs and dampen immune response

Question 20

TGF- B role in cancer immune escape

Answer 20

• tumor cells produce it to help with promotion of T-regs which then dampen the immune response

Question 21

Tregs are _____ for outcome

Answer 21

bad; a higher concetration = shorter life

Question 22

myeloid- derived supressor cells (MDSCs) (cancer immune escape strategy)

Answer 22

• they have many ways in which they inhibit the immune systems
• they are immature myeloid cells
• in certain cancer types, these are increased and associated with poorer prognosis
• have potent inhibitors of effector T cells

Question 23

tumor microenvironment (TME)

Answer 23

• hostile
• very different cells types; highly heterogenous
• they impact the surrounding cells that arent cancer and make them behave abnormally because of the way that cancer is interacting with them
• forexmaple, fibroblasts
• hypoxia, low pH, and glucose (which isnt good for immune system)
• altered metabolite composition (with the arginase 1 metabolic enzyme altering)

Question 24

cancer cells use many escape mechanisms; e.g. acute myeloid leukaemia…..

Answer 24

• immune evasian approaches (like downreg of MHC)
• upregulation of immune checkpoint ligand (PDL1)
• hostile tme
• ## depletion of tryptophan is common because high IDO is present

Question 25

__________ is a hallmark of cancer

Answer 25

Inflammation
- wounds that don’t heal
- acute inflammation is benefiical but a tumor has CHRONIC inflammation which is bad
- chronic inflammation creates a stressful environment which leads to promotion of mutations and enhacings angiogenesis and tissue invasion

Question 26

tumor surveillance vs promotion of inflammation

Answer 26

• differences
• but some overlap;
• for example TNF can be good or bad
• macrophages and neutrophils overlap

Question 27

macrophages (tumor surveillance vs promotion of inflammation)

Answer 27

• tumor-associated ones can be in a form with anti-tumor effects
• others can change behavior to be POLORIZED THAT ENHANCES TUMOR growth (when exposed to hypoxia)

Question 28

neutrophils (tumor surveillance vs promotion of inflammation)

Answer 28

• have 2 faced nature depending on the environment
• can be anti-tumor or pro-tumor depending on properties

Question 29

what changes a macrophage?

Answer 29

• polarisation
• can be from the immune system or actual tumor - they can change it

Question 30

Vaccines for cancer

Answer 30

• already in use (HPV)
• novel vaccines targeting tumor specific and tumor assoicated antigens

Question 31

allogeneic haematopietic stem cell transplation for cancer immunotherapy

Answer 31

• form of transplant for acute myeloid leukemia
• first undertaken as a rescue therapy

Question 32

gene therpies for immunotherapy for cancer

Answer 32

• oncolytic viruses
• T cell receptor genetic modificaiton
• chimeric antigen receptor (CAR) T and NK cells

Question 33

ways to target cancer immune escape

Answer 33

1. target immune checkpoint blockade (make antibodies that can block the PD1 receptors that cancer makes PDL-1 for in order to keep itself proliferating)
2. modulate immunosupressive cells(T-regs or MDSCs by depleting them or inactivating them in some way)
3. block hostile tumor microenvironment
   target tumor promoting inflammation (NFyB signalling by JAKSTAT inhibitors (bc its responsible for driving pro-inflamm cytokines) or inflammatory cytokine antagonist (like an antibody to bind to a pro-inflamm cytokine it will block its activity)