Immune Checkpoint Inhibitors Flashcards
Define Amplitude in the realm of Immunology
In immunology, this refers to
the level of effector output.
-For T cells, this can be levels of cytokine production, proliferation, or target killing
potential.
Define Quality in the realm of Immunology and use CD4+ T-cells as an example.
In immunology, this refers to the type of immune response generated, which is often
defined as the pattern of cytokine production. This, in turn, mediates responses against specific types of pathogen.
For example, CD4+ T cells can be predominantly:
A) TH1 cells
-characterized by IFN-gamma production
-antiviral and antitumour responses
B) TH2 cells
-characterized by IL-4 and IL-13 production
-these cells are important for antihelminth
responses
C) TH17 cells
-characterized IL-17 and IL-22 production
-these cells are important for mucosal bacterial and fungal responses.
Amplitude and Quality of T-cell response is initiated by _______ and regulated by ______ and _____ signals
TCR; co-stimulatory; inhibitory
Steps in T-cell mediated immunity?
1) Clonal selection of antigen specific cells
2) their activation and proliferation in secondary
lymphoid tissues
3) trafficking to sites of antigen and inflammation
4) execution of direct effector functions
5) provision of help (through cytokines and
membrane ligands) for a multitude of effector immune
cells.
Each of these steps is regulated by counterbalancing
stimulatory and inhibitory signals that fine-tune the
response.
What are immune checkpoints?
Why are immune checkpoints important in healthy people?
Immune checkpoints: immune-inhibitory pathways
Under normal physiological conditions, immune checkpoints are crucial for the maintenance of self-tolerance (prevention of autoimmunity) and also to protect tissues from damage when the immune system is responding to pathogenic infection.
Indoleamine 2,3-dioxygenase (IDO) and arginase produced or expressed on which cells?
How do these metabolic enzymes inhibit immune function?
IDO - both tumour cells and infiltrating myeloid cells
Arginase - myeloid-derived suppressor cells
IDO and Arginase inhibit immune responses through:
- local depletion of amino acids that are essential for anabolic functions in lymphocytes (particularly T cells)
- the synthesis of specific natural ligands for cytosolic receptors that can alter lymphocyte functions.
CTLA A) definition B) Expression C) Role for CD8 T cells D) MoA for D E) Role for CD4 T cells F) MoA
A) CTLA4 = cytotoxic T lymphocyte-associated antigen 4 AKA CD152
B) exclusively on T cells
C) primarily regulates the amplitude of the early stages of T cell activation
D) Primarily, CTLA4 counteracts the activity of the T cell
co-stimulatory receptor, CD28.
-Naive or resting T-cell has minimal CTLA4 receptors on the surface but with T-cell activation, CTLA is transported to the T-cell surface via intracellular vesicles and is directly proportional with the strength of the TCR and CD28 stimulation.
-Can sequester CD80 and CD86 from CD28 engagement or actively remove CD80/86 from APC surface.
-May also activate protein phosphatases e.g. SHP2 and PP2A that conteracte kinase signals induced by TCR and CD28
E) downmodulation of helper T cell activity and enhancement of regulatory T (TReg) cell immunosuppressive activity
F) CTLA4 blockade results in a broad enhancement of immune responses that are dependent on helper T cells and, conversely, CTLA4 engagement on TReg cells enhances their suppressive function. CTLA4 is a target gene of the forkhead transcription factor FOXP3
PD1 A) Definition B) Expression C) Role and difference from CTLA4 D) MoA E) Ligands for PD1 F) Role of PD1 inhibitors
A) PD1 = programmed cell death protein 1 AKA CD279
B) Broadly expressed e.g. highly expressed on TReg cells and can be on B cells and NK cells
C) major role of PD1 is to limit the activity of T cells
in peripheral tissues at the time of an inflammatory response to infection and to limit autoimmunity. PD1 predominantly regulates effector T cell activity
within tissue and tumours, whereas CTLA4 predominantly regulates T cell activation
D) PD1 expression is induced when T cells become activated.
-Activated T cells upregulate PD1 and continue to express it in tissues. Inflammatory signals in these tissues –> expression of PD1 ligands –> downregulate the activity of T cells –> limit collateral tissue damage
-best characterized signal for PD1 ligand 1 induction is
interferon‑γ predominantly produced by TH1 cells
-When engaged by one of its ligands, PD1 inhibits
kinases that are involved in T cell activation through
the phosphatase SHP2
-may enhance proliferation of Tregs
E) PDL1 (aka B7‑H1 and CD274) and PDL2 (aka B7‑DC and CD273)
F) Antitumor activity through increase in effector T cell activity, NK cell activity, and PD1+ B cell activity. Possibly decreases Treg activity.
How does T-cell activation occur?
- TCR on naive or resting T-cell binds to the antigen from MHC molecule.
- CD28 = co-stimulatory molecule that binds to the CD 80 (B7.1)and CD 86 (B7.2) ligand on APC but does not affect T cell activation unless the TCR is first engaged by cognate antigen.
- Once antigen recognition occurs, CD28 signalling strongly amplifies TCR signalling to activate T cells.
Role of FOXP3 for T-cells?
-expression of which determines the TReg cell lineage and TReg cells therefore express CTLA4 constitutively.
-encoded on the X chromosome.
-Genes encoding some of these immunecheckpoint
receptors, such as CTLA4, are actually FOXP3 target genes
Define suicide substrates
Molecules that inhibit an enzyme by mimicking its
substrate and covalently binding to the active site.
Name some other immune checkpoints besides PD1 and CTLA4
PDL1 LAG3 B7-H3 B7-Ha TIM3
Define Anergy
A form of T or B cell inactivation in which the cell remains alive but cannot be activated to execute an immune response.
Anergy is usually a reversible state.
Important distinguishing feature of ICI compared to conventional chemo agents and oncogene-targeted smll molecule drugs
Kinetics
-response to be ICB may be up to 6 months after treatment initiation
Define pseudoprogression.
Implications?
metastatic lesions actually increase in size on computed tomography (CT) or magnetic resonance imaging (MRI) scans before regressing, which seems to occur owing to increased immune cell infiltration
Demand reevaluation of response criteria for immunotherapeutics away from the conventional time-to-progression or Response Evaluation Criteria in Solid Tumours (RECIST) objective response criteria, which were developed on the basis of experiences with chemotherapeutic agents and as the primary measure of drug efficacy
