dont know (4) Flashcards
treating lymphoma?
Treating leukaemia (CLL) and lymphoma (DLBCL) tumor cells with anti-PD-L1 or T cells with PD-1 prevents tumour inhibitory signalling and rescues anti-tumor T cell activity.
Mechanisms of PD-L1 pathway-induced immunosuppression in the tumour microenvironment
t cell apoptosis, t cell exhaustion, treg induction.
L20- ICB?
ICB immunotherapy: Immune checkpoint blockade (ICB) immunotherapy (including anti-CTLA-4, anti-PD-1 and anti-PD-L1 antibody drugs) which target and block immune checkpoint molecules can unleash anti-tumor immune responses (T cell activation and effector functions) and has provided a new weapon against cancer.
ICB in the clinic –
Harnessing TME cells to treat cancer
ICB antibodies (anti-CTLA-4, anti-PD-1 and anti-PD-L1) can unleash anti-tumor immunity (T cell activation and effector functions) and mediate durable clinical responses in subsets of patients
Cd8 and cd26 same ligands for cd28- costimulatory receptor so antibodies do not target them for therapy but ctla-4 directly.
Anti-PD-1 antibody ICB immunotherapy (with nivolumab) has substantial clinical activity against melanoma and lymphoma patients.
T cell-mediated lysis (tumour kill)
ICB therapy induces T cell recognition
and lytic immune synapse formation
L20- ICB + future?
Strategies to maintain activated tumour-specific T cells include the use of blocking monoclonal antibodies, such as antibodies targeting either cytotoxic T lymphocyte-associated protein 4 (CTLA4) or programmed cell death 1 (PD1), to neutralize co-inhibitory receptors. Therefore, these antibodies that block intrinsic inhibitory immune checkpoints allow a sustained T cell response, including an increased production of cytokines, such as tumour necrosis factor-α (TNFα), interferon-γ (IFNγ) and granzyme B (lytic immune synapse).
Future of ICB immunotherapy: combination therapy to optimize immunotherapy
Combine ICB with conventional therapies (chemotherapy or radiotherapy).
Combine multiple ICB antibodies e.g. anti-CTLA-4 with anti-PD-1 or anti-PD-L1.
ICB + positive drivers of anti-tumour immune responses
(e.g. co-stimulatory receptor agonist antibodies, vaccines, CAR T cells, targeted drugs – targeting tumour oncogenes).
Can think about vaccines in combination with these anti-pd-1 antibody etc.- good for essay questions.
L20- therapies targeting costimulatory receptors?
a
Co-stimulatory receptor agonist antibodies target the co-stimulatory (‘accelerators’) receptors (signal 2) to positively (+) regulate T cell activation and responses
T cell regulation depends on a balance of positive (co-stimulatory receptors) and negative (immune checkpoints) regulators of T cell activation. Clinical development has focused on the immune checkpoints. However, the positive regulators of T cell activation (diverse co-stimulatory receptors) are also rational targets for cancer immunotherapy. Antibody drugs (agonists) targeting these receptors have shown promise in the early stages of clinical testing (e.g. antibodies: anti-CD28, ICOS, OX40, CD27).
Disadvantage: these immune agonists may induce strong non-specific immune activation (cytokine release syndrome/auto-immunity risk). Have to be tested cautiously.
L14- Class switching?
a
changed by class switching
using Switch regions
* Switch regions proceed each heavy chain gene (except C)
* Contain target sequences for the enzyme AID (Activation Induced
Cytidine Deaminase)
* AID is recruited to the switch regions
* Which ones depends on the initial cytokine stimulus.
* Initiates DNA strand breakage, looping and recombination
DNA breaks initiated by AID causing looping
out of DNA and recombination between
switch regions
Only igm and igD that are close enough to variable regions to be transcribed and produced in absence of class switching. To allow expression of other isotypes need other recombination event.
L12- why do gc reactions take time to mount a diverse specific response?
Gc reactions take time to mount a diverse,specific response: lag period after an infection in primary response. Igm first antibody to be produced as naive b cell is already making it along with igd. Still needs to go through rounds of proliferation and differentiation . production of igg takes longer-about 2 weeks as it requires class switching. But memory cells are retained so that following 2nd infection you get a much more rapid response. Still takes days for secondary response to be mounted as small number of memory cells that need to be activated, differentiate into plasma cells but quicker. Memory cells have already gone through somatic hypermutation, affinity selection and class switching so produce much higher affinity antibodies that are specialised for antigen.
L13- activation into memory?
Memory CD4+ T cells:
* Are selected on high affinity for pathogen (tcr has already been selected)
* Can persist (for long time) in the absence of antigen due to: Specific pro-survival cytokines (IL-7 -> Bcl2) bcl2 activated through il-7 and Altered metabolic reprogramming (IM lecture)
* Have increased clonal precursor frequencies
* Have different recirculation patterns
* Do not divide (or little), but rapid differentiation into
effector upon Ag encounter
* Origin: linear and/or asymmetric division
Memory cells are heterogenous in their location and function.
L13- Tcm, Tem and Trm?
Central memory cells (Tcm) survey peripheral lymphoid
tissue - blood as u can get blood infection so need memory pool that surveys your lymphatic system.
- Express CD62L and CCR7 - same molecules naive t cells express to get into lymph node.
- Low threshold of TCR activation
- Rapid CD40L upregulation
- Slower cytokine responses (compared to other memory
Effector memory cells (Tem) reside in blood and are
recruited to inflamed tissue very efficiently.
- Express integrins (no CD62L and CCR7) and chemokine
receptors -> rapid migration to inflamed tissue
- Low threshold of TCR activation and rapid differentiation
programme.
Tissue resident memory cells (Trm) reside in tissue (for years.)
- Reside in barrier sites – local surveillance
- Express CD69 and CD103 (tissue retention). Dont need signal 1 to be activated.
- Can be activated by “bystander” cytokines
L16- Naive vs memory vs effector T cells and how are they formed?
Naive t cells: few mitochondria, big nucleus. Have excess glucose as they live in the blood where there is lots. Import glucose, perform some oxphos but generally metabolically inactive. Not good at performing glycolysis.
Naive t cells have huge pool of mrna that synthesise effector molecules and enzymes.
Effector t cells: cell bigger, more mitochondria.
metabolic reprogramming provides ATP (energy) (catabolism), synthesise cellular components (anabolism), REGULATE IMMUNE FUNCTION to move through the stages.
L16- How do immune cells use metabolism?
Proliferation, differentiation= increased protein synthesis, lipid demand, atp demand.
Not dependent on glucose but dependent on antigen. Antigen needed for this.
Warburg effect: Normally, cells generate energy (ATP) by using oxidative phosphorylation (OXPHOS), a highly efficient process in the mitochondria that requires oxygen.
The Warburg Effect is when cells switch to generating energy through glycolysis, even when oxygen is present. Glycolysis is less efficient but much faster, and it creates byproducts that are useful for cell growth and division.
Why is this important for immune cells? When T cells or other immune cells are activated (e.g., by encountering an antigen), they need rapid energy and materials for proliferation and effector functions. So, they switch to glycolysis to meet these demands.
Metabolism of effector cells relies on glycolysis and glutaminolysis as they do not have much mitochondria for oxphos. Effector cells use anabolic side e.g: for nucleotides that synthesise dna for dividing. Effector cells do not have much mitochondria so in 24h can synthesise mitochondrial mass. When activated not enough mitochondria to use oxphos effectively.
The carbons from glucose (glutamine) are used for:
* Fast activation – rapid ATP generation (catabolism)
* Generation of metabolites to support proliferation
and differentiation (anabolism)
Effector to memory cells: Lipids -> FAO ->
OXPHOS
Glutaminolysis
Glycolisis
CBP
Mesh of mitochondria in memory cells is more complex. Have the mitochondrial power needed to perform oxphos effectively. Already selected for antigen, have metabolic programme needed to perform it very quickly. Perform little glycolysis.
