Unit 6 - Apoptosis, advanced therapies and concepts of immuno-oncology Flashcards

Question

BCL-2 family function what do they have

Answer 1

central controllers of intrinsic cell death BCL-2 family members have at least 1 of 4 conserved motifs bcl-2 homology 1 - 4' BH1, BH2, BH3, BH4 important in regulating interaction between family members

Answer 2

pro-apoptotic effector proteins - BAX and BAK anti-apoptotic protein - BCL2, BCL-XL, MCL1 pro-apoptotic BH3-only proteins - BID, BAM, BIM, NOXA balance between pro and anti apoptotic BCL-2 family members determines cell fate

Answer 3

BCL2 BCL-XL MCL1

Answer 4

BID BAD BIM NOXA

Answer 5

tumour cells under great stress DNA damage, lack of nutrients, lack of O2 cancer therapies normally induce apoptosis

Answer 6

autoimmune diseases - Lupus, rheumatoid arthritis, type 1 diabetes AIDS, CD4+ lymphocyte depletion

Answer 7

increased expression of anti-apoptotic BCL2 family members elevated XIAP expression (intrinsic) Bax, TSG mutated in some colon tumours p53 is a TSG down regulated in many cancers destruction of pro-apoptotic proteins proteosome degrades proteins and can be over-active in certain cancers

Answer 8

chronic lymphocytic leukemia acute myeloid leukemia...

Answer 9

cell-mediated immunotherapy immune-checkpoint inhibition

Answer 10

neutrophils are by far the most abundant leukocyte circulating - comprise \> 50% of leukocytes adept at phagocytosing and killing microbes

Answer 11

neutrophil eosinophil basophil immature DC mast cell precursor monocyte → macrophage platelet erythrocyte

Answer 12

detecting and instigating immune responses presenting the components of phagocytosed microbes to cells of the lymphoid system escalating immune responses through the secretion of multiple cytokines and chemokines

Answer 13

T and B lymphocytes adaptive immune system can generate highly specific cell surface receptors through genetic recombination of a relatively limited number of precursors for these receptors T cell receptors = TCRs B cell receptors = antibodies both can be highly specific for particular molecular structures (ANTIGENS)

Answer 14

B-cell T-cell NK (mature DC)

Answer 15

innate immune system police presence of special antigen-presenting molecules (MHC I) use germline-encoded receptors (NK receptors) that are distinct from the receptors of T and B cells and are endowed with the ability to kill cells that express **abnormal MHC receptor profiles**, as well as **stress induced molecules** T cells recognise infected or tumour cells in an antigen dependent manner NK cells recognise infected or tumour cells in an antigen independent manner (no need for antigen exposure or immunological memory)

Answer 16

T cells recognise infected cells in antigen **dependent** manner NK cells recognise infected cells in antigen **independent** manner

Answer 17

infection occurs → innate serves as a rapid rxn force that deploys a range of relatively non-specific weapons to eradicate the infectious agent or at the very least to keep the infection contained gives time for initially sluggish adaptive immune system to select and clonally expand lymphocytes with receptors (TCR and antibodies) that are capable of making a much more specific response that is uniquely tailored to the infectious agent - adds new weapons to the attack

Answer 18

detect infectious agents - an array of pathogen recognition receptors (PRRs) borne on their plasma membranes e.g. Toll-like receptors as well as other cellular components such as endosomes DON'T RECOGNISE ANTIGENS, instead: Pathogen Associated Molecular Patterns (PAMPs) Danger Associated Molecular Patterns (DAMPs) examples include certain sugars not seen in humans e.g. lipopolysaccharide (LPS/endotoxin - cell wall of bacteria), nucleic acids dying cells also release factors capable of activating PRRs

Answer 19

1. macrophage is put on a state of high alert (activated) and is now better at engulfing (phagocytosis) and killing any microorganisms it encounters 2. macrophage begins to secrete cytokines and chemokines, which enhance vascular permeability and attract other immune cells to cause inflammatory response

Answer 20

cytokines produced by macrophages induce expression of receptors on endothelial cells (**selectins**) that bind to ligands on neutrophils causing them to decelerate on the BV wall chemical attractants (**chemokines**) attract into tissues - WBCs slow down when interacting with these - sense chemokines - chemicals released under tissue - activation of molecules on neutrophil - attaches to endothelial lining and then migrates out - into deeper tissues where inflammatory stimulus is coming from migration is facilitated by strong adhesion molecules on the neutrophils - **integrins**

Answer 21

inspect host cells for signs of abnormal patterns of protein expression that may indicate that such cells might be harboring a virus - immunosurveillance capable of killing cells that have suffered mutations and are on the way to malignant transformation into tumours health cells express MHC molecules - NK cells have inhibitory receptors which recognise MHC - if cells lose MHC, they are vulnerable to killing by NK cells (missing self) predominant mode of killing = release of cytotoxic granules containing lytic proteases Perforin and Granzyme NK cells also release cytokines to activate immune response genetic instability (as a result of cancer) and/or viral infection can lead to expression of protein ligands that are recognised by activating receptors on NK cells

Answer 22

antibody coated cells via their Fc receptors, targeting them for destruction (antigen dependent cytotoxicity) B cells are the source of antibodies once activated, NK cells can also kill target cells via expression of death inducing ligands, which induce apoptosis (FAS or TRAIL)

Answer 23

**cytokines** produced by macrophages can activate NK cells NK cells can recognise PAMPs and DAMPs e.g. nucleic acids from dying cells cytokines released by activated NK cells important for maturation of dendritic cells and in turn enhance macrophage function

Answer 24

when NK cells kill cancer cells, the antigens released are taken up by **antigen presenting cells - dendritic cells** **cytokines** produced by NK cells stimulate **maturation of dendritic cells** mature dendritic cells present tumour antigens in association with their MHC molecules to helper (CD4) and cytotoxic (CD8) T cells CD8 cytotoxic cells can then recognise and kill antigen expressing tumour cells CD4 T cells help B cells produce antibodies against these antigens

Answer 25

dendritic cells

Answer 26

DCs are produced primarily in the bone marrow and derive their name from the multiple long membrane projections or dendrites that these cells possess they share a common progenitor with macrophages both macrophages and DCs have somewhat overlapping functions

Answer 27

mediated by lymphocytes → T lymphocytes (T cells) → B lymphocytes (B cells)

Answer 28

defining characteristics of the acquired immune response both highly antigen specific both exhibit immunological memory whereby they respond more vigorously upon re-encounter with specific antigen

Answer 29

from bone marrow precursors in the thymus

Answer 30

1. providing assistance to other cells in the immune response - **helper T cells** 2. Limiting excessive or undesired immune responses – **regulatory T cells** 3. killing cells infecting with pathogens - **cytotoxic T cells**

Answer 31

develop fully within bone marrow produce antibodies - humoral immunity

Answer 32

specific acquired immune response

Answer 33

3-D shape that is complementary to antibody molecules that act as the antigen receptor on B lymphocytes antigen-specific antibody molecules are subsequently released in a soluble (secreted) version by plasma cells derived from B cells following their activation antigens can be proteins, CHOs, lipids, nucleic acids, small molecules

Answer 34

T cells usually in form of proteins that are digested from the original polypeptide into short peptides peptides are then shown to the antigen receptor on the surface of T cells using a MHC which is specialised to show peptides to the T cell receptor (TCR) T cell therefore recognises a shape that is a combination of antigen-derived peptide and MHC

Answer 35

variable region - devoted to binding to the individual antigen **(antigen recognition function)** constant region - concerned with linking to the complement, phagocytes (e.g. macrophages) and NK cells **(effector function)** body must make millions of antibody molecules with different antigen-recognition sites but that all share the property of recruiting other elements of the immune response

Answer 36

ADCC = Antigen Dependent Cellular Cytotoxicity

Answer 37

when the antigen binds to a complementary B cell receptor - a complex containing an antibody on the surface of the B cells → activating signal leading to increased proliferation and survival of B cell

Answer 38

takes place in germline centre of lymph node where Follicular Dendritic Cells present antigen to the B cells only those cells that receive the strongest survival signal due to the best antigen-antibody fit are selected and survive - others undergo apoptosis further help from helper T cells enable the selected B cells to mature into either anitbody producing plasma cells or memory B cells, which are primed waiting to mount a rapid antibody response in case the antigen is encountered in the future

Answer 39

genetic locus that control histocompatability in early transplantation experiments, the donor and recipient were found to need the same MHC locus in order to avoid graft rejection MHC molecules are recognised by T cells via TCRs MHC = polygenic and polymorphic 3 regions = class I (contains genes encoding 6 MHC proteins) and class II (variable number of genes that ultimately encode 3 heterodimeric MHC proteins) MHC genes are highly polymorphic with 1000s of different alleles within population MHC antigens in humans = HLA antigens (human leukocyte antigens) as they were first identified on WBCs

Answer 40

HLA antigens

Answer 41

T cells express TCRs - recognise antigens being presented by MHC molecules CD8 + T cells recognised internally derived antigen being presented on MHC class I molecules allowing CD8 + T cells to scan cells for internal threats CD4 + T cells recognise endocytosed antigen presented on MHC class II molecules of professional anitgen-presenting cells, thereby allowing recognition of EC antigens

Answer 42

highly variable heterodimer consisting of either α and β OR γ and δ chains these chains undergo random rearrangement at the genetic level to generate a wide variety of TCRs

Answer 43

αβ TCRs with which they recognise their antigen being presented by MHC

Answer 44

forms a complex with CD3 molecules TCR itself has a short cytoplasmic tail with no signalling capability it forms a complex with CD3γ, δ, ε and ζ chains the cytoplasmic tail of CD3ζ contains an immunoreceptor tyrosine-based activation motif (ITAM), which is phosphorylated, allowing it to signal

Answer 45

immunoreceptor tyrosine-based activation motif (ITAM), which is phosphorylated, allowing it to signal

Answer 46

similar to Fab fragments of B-cell receptors/antibodies both composed of 2 different peptide chains and have variable regions for binding antigen, constant regions and hinge regions principal differences - **TCRs** remain **membrane bound** and contain only a **single antigen-binding site**

Answer 47

TCR is assisted by CD4 or CD8 receptors recognises peptide antigen in context of MHC molecules TCR activation signals are propogated via the CD3 co-receptor complex, which is made up of CD3 γ, δ, ε and ζ chains co-clustering of CD4 or CD8 with the TCR complex facilitates signal propogation through phosphorylation of immunoreceptor tyrosine-based activation motifs (ITAMs) with the CD3 ζ chain

Answer 48

initial stable interaction between APCs or target cells and T cells following antigen recognition is facilitated by adhesion molecules, which causes cells to stick more tightly together in addition to antigen recognition via TCR along with CD3 signalling, T cells require a 2nd activating signal (signal 2) to fully activate and avoid anergy (unresponsive) or apoptosis co-stimulatory molecules on APC's bind to CD28 and this provides this 2nd signal by upregulating an anti-apoptotic protein Bcl-xL, CD28 stimulation blocks TCR-mediated signals that would otherwise result in apoptosis **(activation-induced cell death)**

Answer 49

provide signal 3 to promote clonal expansion and proliferation further stimulation and activation (signal 3) can be provided by cytokines e.g. IL 2 (released by dendritic cells or macrophages)

Answer 50

initial stable interaction between APCs or target cells and T lymphocytes following antigen recognition is facilitated by adhesion molecules, which cause cells to stick more tightly together

Answer 51

NB NK cells - innate killers Antigen independent Recognise virally infected cell or tumour cell because it has 1. Lost MHC molecule 2. Upregulated stress molecules - danger associated molecular patterns - ABNORMAL Adaptive response - B cells produce antibodies - NK cells may further contribute to ongoing immune response through ADCC Virally Infected or cancer cells - sometimes downregulate MHC class I so T cells no longer recognise them but this then makes them vulnerable to killing by NK cells

Answer 52

uncontrolled T cell activation could be very harmful and lead to autoimmune disease dampening down of T cell responses occurs via a number of mechanisms, some of which operate at the level of the actvated T cell itself, while others operate via additional T cell subsets - regulatory T cells molecules present on activated T cells that serve as "off switches" for such T cells represent important immunological checkpoints, helping to keep T cell responses within certain limits

Answer 53

immune checkpoint receptors - PD-1 and CTLA4 ligands - PD-L1 and CD80/86 T cells expressing these molecules are suppressed - molecules are ligated by PD L1 Propogation of inhibitory signals in T cell that turns off T cell cycle - no further cytotoxic T cell activation Important in normal homeostasis in cancer this is exploited by tumour - T cell exhaustion

Answer 54

signalling via TCR and CD28 leads to T cell activation inhibitory receptors or "immune checkpoints" e.g. CTLA-4 and PD-1 are upreg. on activated T cells, usually after prolonged activation in the presence of their ligands on APC's or tumour cells can induce T cell inhibition activated T cells upregulate Fas receptor in absence of co-stimulation by CD28 Fas ligand expressing cells can induce apoptosis (activation induced cell death)

Answer 55

Tregs are able to suppress T cell activation by expressing ligands for immune checkpoints, releasing suppressive cytokines or eliminating effector CD8/CD4 T cells Tregs are important in preventing autoreactivity (autoimmune disease) in **cancer**, Tregs are often **over-active**, leading to an impaired immune response

Answer 56

immune system has evolved to deal with infection (non-self antigens) rather than cancer (altered self) recognising and mounting a robust immune response against mutated cancer cells that may only have subtle differences from normal cells is challenging mutational processes associated with the development of cancer frequently generates neoantigens that, in principle, can elicit T cell responses, in practice such responses are highly muted because of mechanisms that serve to prevent the emergence of autoimmunity

Answer 57

well-meaning regulatory T cell responses and other mechanisms that serve to limit the development of autoimmunity (such as CTLA-4 and PD-1 mediated downregulation of T cell responses) conspire to suppress the immune response against cancer tumours also actively manipulate the immune system to minimise immune responses that do emerge tumours recruit macrophages, neutrophils and other innate immune cells and "re-educate" such cells towards a wound-healing phenotype for the purposes of supporting tumour growth and survival "cancer = wound that does not heal"

Answer 58

gradual stepwise development of tumours over long periods of time permits the selection of cells that are effectively invisible to the immune system - must avoid killing by immune system if they are not, such cells are weeded out by the immune system as the tumour develops this process selects for the "fittest" tumours that are very difficult for the immune system to deal with

Answer 59

in the absence of sufficient activation Cytotoxic T cells can't deal with cancer Antigens taken up by dendritic cells Co-stim. signals Proper functioning T cells If dendritic cells take up antigen - various cytokines T cells - recognised antigen but cannot mount response

Answer 60

loss of MHC expression by cancer cells means T cells unable to recognise tumour antigen however this can make them vulnerable to NK cells expression of certain ligands can either suppress (e.g. PD-L1) or kill (Fas Ligand) immune cells

Answer 61

T cell checkpoint molecules (CTLA-4, PD-1) are frequently engaged by tumours to suppress anti-tumour T cell responses cancer cells frequently engage immune checkpoint molecules on T cells, such as PD-1 and CTLA-4, which has the effect of anergizing T cells in the tumour environment blocking antibodies against CTLA-4, PD-1 and PD-L1 can reactivate tumour-specific T cells and can now play a role in treatment of solid cancers

Answer 62

1. passive immunotherapy with monoclonal antibodies 2. unmasking of latent T cell responses by targeting immune checkpoint molecules 3. antigen-independent cytokine therapy 4. vaccination approaches to stimulate immune responses against tumour antigens or the tumour vasculature 5. adoptive transfer of ex vivo expanded T, NK or DCs 6. adoptive transfer of ex vivo generated chimeric antigen receptor (CAR) T cells 7. bispecific T cell engagers

Answer 63

Recognition by NK via Fc receptor NK recognises Fc - release cytotoxic granules - perforin forms pores in tumour cells to allow other contents in - lysis

Answer 64

CD20 = antigen present on mature B cells when CD20 antibodies bind to CD20 antigens on surface of malignant B cells it can induce cell death by: fixing complement leading to cell lysis direct apoptotic signals ADCC (NK cells) phagocytosis (macrophages bind antibody via Fc receptors)

Answer 65

CTLA-4, PD-1 and PD-L1 blocking antibodies

Answer 66

CD20 antibody non-hodgkins lymphoma chronic lymphocytic leukemia

Answer 67

acute lymphoblastic leukemia no MHC needed

Answer 68

In normal t cell receptor CD28 would be needed for co stim. But all built in car t cell molecule - recognises tumour cell antigen even in absence of MHC - sufficient to activate killing by T cell

Answer 69

HIV - retroviruses - good at stable genetic modification Leukapheresis - T cells extracted and we put in retrovirus that can genetically express Need cytokines to proliferate and expand After chemotherapy (done to get rid of lymphocytes)

Answer 70

BCMA represents a good target for immunotherapy * Can recognise Tumour antigen (BCMA) * Other arm - recognises CD3 * Brings t cell to close proximity to target cell and leads to recognition of tumour cell by t cell - recognition and release

Answer 71

CAR T cells bispecific T cell engagers bispecific antibodies antibody-drug conjugates

Unit 6 - Apoptosis, advanced therapies and concepts of immuno-oncology Flashcards

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