immune check point receptors Flashcards
what are immune checkpoints
inhib receptors expressed on immune cells that trigger immunosuppressives signalling pathways
what are inhibitory receptors essential for
essential for limiting effector immune responses to prevent collateral tissue damage and restore tissue tolerance
cytotoxic t lymphocyte antigen 4
immunoglobulin domain containing transmembrane protein
only expressed on activated t cells
competes with cd28 to bind b7 ligands cd80 and cd86
signals cells intrinsically to reduce tcr and cd28 binding
how does ctla 4 work intrinsically
intrinsic control
- inhibitory signalling
- ctla4 signalling can interfere with proximal signalling by the tcr and cd28
- competition for ligands
- ctla4 is the higher affinity receptor than cd28 for cd80 and cd86
- promote adhesion or reduced stop signal
- ctla 4 can increase t cell / apc adhesion through a pathway mediated by lfa1 and decrease duration of apc/ t cell interaction by inhibiting tcr mediated stop signal and results in reduced t cell activation
- ligand independent signalling
- ctla4 splice variant that cannot bind to ligands can inhibit t cell activation through a similar signalling pathway as full length ctla4
how deos ctla4 work extrinsically
- reverse signals through ligands into apc
- clta4 can reverse signalling through cd80 and cd86 into apcs leading to IDO production and suppression of t cell effector responses
- reduce ligand expression / availability
- secreted faxcxtors such as il10 tgfb or splice variants of ctla4 reduce ligand expression or availability
- ctla4 removes ligands from apcs
- ctla4 binding to cd80 orcd86 can result in transendocytosis of the ligand from the apc resulting in lower levels of ligands on the surface of apcs
ipilimumab
anti-ctla4 against advanced metastatic melanoma control was treatment of a peptide gp100 cancer doesnt come back better response rate when administered earlier
programmed cell death protein 1
pd-1
belongs to immunoglobulin superfamily
expressed on ts, bs, nks, dcs and activated monocytes
upregulated upon tcr activation
two ligands
pdl1 expressed constitutively on ts bs macros and dcs
pdl2 contributes to pd1 mediated inhibition
how does pd1 work
2 motifs - itim and itsm
both remove tyrosine phosphatases
remove from tcr downstreams swich off pi3k and plcy1 pathways
this allows survival, cytokine production, expression of tfs, cell cycle progression and aerobic glycolysis
nivolumab
anti pd-1
pd-1 blockade has proven to be effective in several cancers
adverse effects of immune check point blockade vary between patients
future immune checkpoint blockade
therapeutic activity of immune checkpoint inhibs is the result of complex interplay between multiple factors in the tumour, tumour micro environ and immune system
treatment response are variable so predictive biomarkers of favourable response need to be identified
limiting toxicity needs to be researched
lymphocyte activating gene 3
LAG3
kieele motif is important to fucntion
lad3 and pd-1 are often expressed on exhausted t cells and combined blockade cures mice of most tumours
adverse effects of icb involve musocal sites
immune adverse events occur in upto 90% of anti ctla4 antibody treated patients and 70% of ati pd1/pdl1 antibodies
originate in the skin, gi tract, liver and endocrine system
loss of pd1:pdl1 inhib pathway breaks cd8 t cell tolerance to intestinal self ag in mice leading to severe enteric autoimmunity
iel express many inhib receptors
hypothesis of iel and immune checkpoint receptors
iel and constitutively active yet resting cells
recent data suggests tcr on iel is constitutively engaged by self antigens on epithelial cells
