Chapter 21 Flashcards
Which cells express MCH class 2?
CD, macrophages and B-cells
Which of the 3 pathways of peptide binding are there, which T-cell is activated by which and which pathway is most important for recognition of tumour antigens?
Exogenous - bind to MCH 2 and activate CD 4 + cells, endogenous - bind to MHC 1 (all cells) and activate CD 8+ cells, cross-over pathway display exogenous peptides on MCH 1 and activate CD 8+ cells - this is the most important pathway for recognition of tumour antogens taken up from tumour apoptotic bodies.
What is the Mao for imiquimod?
It activates toll like receptors 7 which result in production of interferon-alpha.
INF-alpha induce apoptosis of tumour cells; enhances effect of CTL and NK cells, modulate MHC expression and inhibit tumour angiogenesis
How are APCs activated/matured?
By activation of special cell surface receptors or intracellular receptors that recognise PAMPS, these include TLRs, NODs, RIG-1
Which lymphocyte has the ability to react to unprocessed antigen, and which will only respond to peptides bound to MHC on APCs?
B cells can respond to unprocessed antigens, and T cells to the APCs
Where do you find gamma/delta T cells?
Intestine and skin
Memory T cells are ______ positive and can be divided into 2 subtypes ___________ and __________.
CD8+, effector memory and central memory cells.
Which IL is essential for T cell proliferation and survival?
IL-2
What are tumour-associated antigens?
Antigens expressed preferentially on tumour cells, but often can be expressed on normal cells too
Name the 6 different categories of tumor associated antigenes?
Mutated, cancer testis, differentiation, overexpressed, viral , postranscriptionally modified
What are the 3 phases of immunosurveillance?
Elimination, equilibrium, escape
Name some mechanisms for how tumours can escape the immune system?
Reduce expression TAA, down regulate MCH class 1, negative regulatory immune cell types, immunosuppressive factors produced by tumour cells, surface receptors that reduce T-cell response
Which mechanisms may lead to failure of immune-mediated tumour control?
The same mechanisms which regulate autoimmunity; T-cell deletion, T-cell anergy, the function of negative regulatory cells and molecules
Name two examples of tumour related immunosuppressive factors?
TGF-beta and IDO
Which cells produce TGF-beta?
Tumor associated macrophages and Tregs
What is the result of increased TGF-beta production by tumour associated macrophages?
Reduced DC activity by dowregulation MHC and surface DCs. It inhibits IL-12 production (important pro-inflammatory cytokine), interferon-alpha and tumour necrosis factor (TNF-alfa).
How does the enzyme IDO excert immunosuppressive effect?
IDO is involved in oxidative catabolism of tryptophan, which is important for. T-cell proliferation and activation. Depletion of tryptophan by IDO activity will therefore result in reduced t-cell activity and response.
Name 3 strategies for non-specific immunotherapy?
The use of cytokines, immunological adjuvants and agents that target immunomodulatory molecules.
Name 5 examples of nonspecific immunotherapies?
Bacillus of calmette and guerin (BCG) Interferon alpha IL-2 Imiqiumod Anti-CTLA-4 blockade
Name 3 examples of specific immunotherapies
Tumour associated peptides, tumour associated proteins, irradiated tumour cells
Name 4 examples of adoptive cell therapies
Dendritic cell
Sipuleucel-T
T-cell clones
Tumour infiltrating lymphocytes
Alemtuzumab; cancer, molecules, type of mAB
CLL, CD5, Humanized IgG1
Bevacizumab; cancer, molecules, type of mAB
Colorectal, lung cancer; VEGF; humanised IgG1
Cetuximab; cancer, molecules, type of mAB
Colorectal cancer, EFGR, chimeric IgG1
Gemutzumab; cancer, molecules, type of mAB
AML, CD33, Humanized IgG4
Ibritumomab tiuxetan: cancer, molecules, type of mAB
non-hodgkin lymphoma, CD20, mouse
Ofatumumab; cancer, molecules, type of mAB
CLL, CD20, Human IgG1
Panitumumab, cancer, molecules, type of mAB
colorectal cancer, EGFR, human IgG2
Rituximab, cancer, molecules, type of mAB
Non-hogkins, CLL, CD20, Chimeric IgG1
Tositumomab, cancer, molecules, type of mAB
Non Hodgkin, CD20, mouse
Trastuzumab, breast cancer, Her-2/neu, humanised IgG1
Define chimeric, humanised and human antibodies
Chimeric- the variable fragment of the antibody molecule is of mouse origin and the constant region is human
Humanised- only the hyper variable region is of mice origin, the rest of the AB is human
Human- the AB is fully human, usually produced in Chinese hamster ovary (CHO) cells with the desired ab gene.
By which mechanisms can antibodies work?
- Block receptor signalling
- Trigger receptor signalling
- Induce cell lysis by activating complement protein cascade or initiation of antibody-dependent cell mediated cytotoxicity
- Enhance T-cell priming
Give an example of a mAB which work both by inhibiting cell signalling and through antibody-dependent cell mediated cytotoxicity?
Trastuzumab
How may mAb lead to enhanced T-cell priming?
Lysis of tumour cells result in fragments of the tumour cells, they may bind to TAA-specific antibodies. The complexes can be recognised by FcRs expressed in DCs, and the TAA derived peptides presented to T-cells via cross-presentation
Explain antigen-depended cell-mediated cytotoxicity (ADCC)?
The AB bind to a TAA on the tumour cell, the AB is the bound by the FcR, which trigger the cytolytic activity of the NK cell
Explain how use of mAB can cause complement activation?
The AB binds to TAA on the tumour cell, a complement protein bind to the Fc domain of the AB/AG complex resulting in a cascade ending in MAC formation which causes pore formation and cell death by lysis.
How can
How can T-regs suppress the immune system?
- Directly by killing T-cell and APCs via granzyme B production - reduces the t-cell activity and APC activity
- Inhibit the ability of effector CTL to kill cells by inhibit release of granzymes
- Increase IDO production - which inhibit T-cell proliferation
- Bind IL2- inhibit T-cell proliferation
- Produce IL-10 and TGF-beta - stimulate differentiation of more Tregs
What are the 5 mechanisms tumour cells induce immunosuppression?
- Avoid immune activation - by increasing inhibitory checkpoint molecules, increase production immunosuppressive cytokines, reduce MHC expression on the cell surface
- Attract MDSC - by inducing inflammation and release from bone marrow via IL-13 and GM-CSF
- Activate T-regs
- Alter DC- effect
- produce immunosuppresive cytokines
