L30 Tumour Immunology Flashcards
How does the immune system discriminate self from non-self
Central and periperial tolerance- it makes it hard for immune system to detect cancer because they are ‘altered self’
central tolerance
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
peripheral tolerance
induces anergy in mature B and T cells
- supresses T cells
‘Coley’s toxins’
- 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’
Mice models that showed immune/tumor link
- 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)
Transplant patients show immune/tumor link becuase…
they have higher tumor incidence and they are immune supressed typically
presence of _____ correlates with better prognosis (showing immune/tumor link)
Tumor infiltrating lymphocytes (TILs) which are b and t cells
tumor antigens recognized by T cells
tumor specific antigens and tumor associated antigens
tumor specific antigens
- 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
tumor associated antigens
- 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)
immune editing of tumors
selective pressure favors tumor variants that ESCAPE immune dectection
Evasion (cancer immune escape strategy)
- 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)
Inhibitory immune receptors (cancer immune escape strategy)
- 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
PD-L1
- 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
metabolic enzymes (cancer immune escape strategy)
- IDO or aginase 1 examples
- breakdown crutial amino acids that amino acids need to proliferate, so they limit them from developing
Indoleamine dioxygenase (IDO)
- a metabolic enzyme that leads to tryptophan depletions and starves T cells to keep them from developing
arginase 1
- a metabolic enzyme that lead to arginine depletion and starves T cells to keep them from devleoping
regulatory T cells (cancer immune escape strategy)
- 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
CCL22
- a chemokine that cancer uses to attract T-regs and dampen immune response
TGF- B role in cancer immune escape
- tumor cells produce it to help with promotion of T-regs which then dampen the immune response
Tregs are _____ for outcome
bad; a higher concetration = shorter life
myeloid- derived supressor cells (MDSCs) (cancer immune escape strategy)
- 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
tumor microenvironment (TME)
- 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)
cancer cells use many escape mechanisms; e.g. acute myeloid leukaemia…..
- 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
__________ is a hallmark of cancer
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
tumor surveillance vs promotion of inflammation
- differences
- but some overlap;
- for example TNF can be good or bad
- macrophages and neutrophils overlap
macrophages (tumor surveillance vs promotion of inflammation)
- 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)
neutrophils (tumor surveillance vs promotion of inflammation)
- have 2 faced nature depending on the environment
- can be anti-tumor or pro-tumor depending on properties
what changes a macrophage?
- polarisation
- can be from the immune system or actual tumor - they can change it
Vaccines for cancer
- already in use (HPV)
- novel vaccines targeting tumor specific and tumor assoicated antigens
allogeneic haematopietic stem cell transplation for cancer immunotherapy
- form of transplant for acute myeloid leukemia
- first undertaken as a rescue therapy
gene therpies for immunotherapy for cancer
- oncolytic viruses
- T cell receptor genetic modificaiton
- chimeric antigen receptor (CAR) T and NK cells
ways to target cancer immune escape
- target immune checkpoint blockade (make antibodies that can block the PD1 receptors that cancer makes PDL-1 for in order to keep itself proliferating)
- modulate immunosupressive cells(T-regs or MDSCs by depleting them or inactivating them in some way)
- 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)
