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22 spring: immunology > Unit 4: tumor > Flashcards

Unit 4: tumor Flashcards

1
Q

evidence that tumors are immunogenic

A

Immune compromised animals have an increased incidence of tumor
development (epithelial tumors, lymphomas, leukemias etc)

Tumor antigen-specific T cells present in tumor bearing hosts

Spontaneous regression of established tumors

Response of some tumors to non-specific immune activation (e.g. post surgical infections in OSA; Coley’s toxins)

Presence of tumor antigen escape variants suggest immunological pressure

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2
Q

Cytotoxic T cell infiltrates confer ___ prognosis

A

favorable

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3
Q

Regulatory T cell infiltrates confer ___ prognosis

A

poor

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4
Q

Tumor Immunogenicity depends on tumor __

A

mutational load

as tumors grow- they will change and develop mutations that can be attacked by the body

tumors caused by carcinogens have more mutations and more reactions to T cells

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5
Q
A

anti PD-1 therapy

give drug that prevents T cells from being turned off → leading to immune response that shrinks the tumor

Blockade of inhibitory T cell signals leads to dramatic therapeutic responses in human patients with refractory melanoma

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6
Q

___ collaborate to protect against development of carcinogen-induced sarcomas and spontaneous epithelial carcinomas

A

Lymphocytes and IFN-γ

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7
Q

Immune attack leads to the selection of tumor cells that are ___, which explains the apparent paradox of tumor formation in immunologically intact individuals.

A

more capable of surviving in an immunocompetent host

body kills weak tumor cells, strong survive to live and spread

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8
Q

Concept of Immune Surveillance & Immune editing

A
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9
Q

The Tumor Microenvironment is profoundly immune suppressive and largely responsible for ineffective ___

A

T cell responses

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10
Q

Addressing the immune suppressive Tumor Microenvironment is essential for effective ___

A

anti-tumor immunity

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11
Q

Why does anti-tumor immunity fail?
• Lack of ___(down regulation of MHCI)

  • Changes in TAA and antigen-presentation capacity – mutations or silencing of genes involved in ___
  • Tumor antigen ___ (mucopolysaccharides, fibrin)
A

TCR recognition

IFN-γ response

masking

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12
Q

Why does anti-tumor immunity fail?
Lack of sufficient T cell activation, failure of __ of antigen-specific T cells

  • ___ of immune activation by tumor
  • Suppression of activation by ___ in TME
A

clonal expansion

Suppression

inhibitory cells/mediators

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13
Q

Why does anti-tumor immunity fail?
T cell exclusion from TME

• Changes in tumor susceptibility to the cytotoxic response – less susceptible to apoptotic and necrotic effects (up-regulation of anti-apoptotic proteins or loss of death receptors, eg. ___)

A

TRAIL receptors or FAS

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14
Q

The Tumor Microenvironment is profoundly immune suppressive and largely responsible for ineffective T cell responses

A

Regulatory Immune Cells

Immune Suppressive cytokines and enzymes

Checkpoint molecules

Tumor Stroma

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15
Q

(Tregs, Myeloid Derived Suppressor Cells (MDSC), TAM

A

Regulatory Immune Cells

The Tumor Microenvironment is profoundly immune suppressive and largely responsible for ineffective T cell responses

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16
Q

(IL-10, TGF-B, IL-35, IDO, arginase etc.)

A

Immune Suppressive cytokines and enzymes

The Tumor Microenvironment is profoundly immune suppressive and largely responsible for ineffective T cell responses

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17
Q

(CTLA-4, PD-1, PD-L1)

A

Checkpoint molecules (CTLA-4, PD-1, PD-L1)

The Tumor Microenvironment is profoundly immune suppressive and largely responsible for ineffective T cell responses

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18
Q

two ways regulatory T cells can suppress

A

dominant consumption of IL2- reg 2 produce a lot of CD25 which use up IL2

Inhibitory cytokines- Treg produce inhibitory cytokines TGFB, IL10 and IL35 that will prevent effector T cells from acting normal

induction of apoptosis- Treg have lots of FAS that will bind to and kill T cells

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19
Q

two major type of MDSC

A

Monocytic (M-MDSC) and PMN (PMN-MDSC)

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20
Q

PMN-MDSC –

A

share phenotypic and morphological features with neutrophils

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21
Q

M-MDSC -

A

similar to monocytes; can differentiate to immunosuppressive
macrophages (TAMs/ M2) and tolerogenic dendritic cells in the TME

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22
Q

MDSCs do not differentiate into immunogenic ___

A

DCs or inflammatory macrophages

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23
Q

In solid cancers, (melanoma, renal, lung, prostate) – increased ___ in circulation – correlates with tumor stage, volume and prognosis.

A

MDSC

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24
Q

of circulating __is a prognostic factor in DLBCL (especially PMN-MDSC)

A

MDSCs

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25
MDSC have Direct suppressive effect on\_\_\_responses
NK and CTL
26
MDSC have NOS and ROS nitration of the TCR on CTLs preventing ___ interaction
MHC
27
In MDSC, Arginase depletes extracellular arginine, preventing\_\_\_cell activation
CD8 and CD4 T
28
Arginase helps expand ___ population
Treg
29
M2 monocytes
tissue repair and angiogenesis tumor promotion down regulation of M1 and adaptive immunity
30
TAM are type ___ and are involved in\_\_\_
M2 monocytes metastasis, down regulation of adaptive immunity and tumor production
31
IL 10 is made by __ and does what
32
IDO is made by ___ and does \_\_\_
33
immune checkpoints
**down regulate immune response** after elimination of disease ## Footnote Prevent too strong an immune response that may damage normal tissues Maintain **immune tolerance/peripheral tolerance** to self antigens Many have been identified, but **CTLA-4 and PD-1** are the two that have been best characterized Mouse models in which either CTLA-4 or PD-1 has been deleted results in **systemic autoimmunity**
34
CTLA-4
checkpoint that stops cell from starting CTLA found on **T cell**, will interact with CD80/86 and will **inhibit/turn off the T cell** CTLA found on **Treg** will cause **activate** in function of **Treg**
35
PD-1
checkpoint that stoped “car” as it is driving down the road when T cell activated, PD-1 upregulated, will bind to PD ligand and will turn off T cell
36
CTLA-4 has higher affinity for ___ interrupting activation signal, downregulating T cell function and inhibiting excessive T cell expansion
CD80/86,
37
In the TME, tumor-specific T cells are inactivated by ___ on the tumor cell resulting in tolerance/anergy
PD-L1 or PD-L2
38
Cancer cells exist in a \_\_\_relationship with their local microenvironment
symbiotic
39
The ___ is complex, and like tumor cells, evolves in response to environmental pressures
microenvironment
40
Standard therapies do not address the\_\_\_ and its contribution to oncogenesis/tumor cell survival
local immunosuppression
41
Failure of anti-cancer therapies to eradicate tumor cells, especially in the setting of metastatic disease, is likely in part due to the presence of ___ in the tumor microenvironment
immunosuppression
42
Improved efficacy of immunotherapy will likely require combination therapies to address the \_\_
TME
43
The goal of cancer immunotherapy is to initiate / augment a self-propagating cycle of anti-tumor immunity that further ___ responses
amplifies and broadens tumor-specific T cell
44
steps of cancer immunity cycle
45
tumor associated antigens
found on tumor cells and normal cells Qualitative and quantitative differences distinguish normal from abnormal
46
how do autologous and allogenic whole tumor cell vaccines work
take out tumor change it, put part of it back in, will either start Tcell response or will be eaten by APC and antigen is presented and starts a T cell response polycolonal CD4 and CD8 response These tumor specific t cells, taken out, multiply in lab and then giving back to body
47
peptide vaccine
supply short amino acid sequence, which sits in MHC groove on ATC only work for specific MHC haplotypes not as popular in vet cause MHC not well understood
48
oncept
DNA vaccine for melanoma with human tyrosinase in it
49
DNA vaccine
have plasmid (circle of DNA) codes for tumor antigen eaten by APC and presented to cause Tumor specific T cell reaction
50
explain
remove tumor sequence and look for mutations that result in new protein take all the changes, and link together and give back to body as DNA vaccination against it
51
two things that can be used as biological vector to deliver tumor associated antigen
Adenoviral vectors Listeria monocytogenes based vaccines
52
adenoviral vector
used to deliver TAA(tumor associated antigens) DNA into cell generates cytotoxic T cell responses against TAA eg. Telomerase
53
listeria monocytogenes based vaccines
change bacteria so that it is not harmful and so it expresses the tumor associated antigen of interest delivers TAA into MHC 1 and II processing pathway generates potent CD4 and CD8 T cell responses against TAA MHC 1→ CD8 MHC 2→ CD4
54
MHC 1→ \_\_ MHC 2→ \_\_\_
MHC 1→ CD8 MHC 2→ CD4
55
canine OSA vaccine
listeria monocytogenes expressing HER2 will be eaten by cell and cause CD4 and CD8 T cell immunity vaccine helped reduce formation of tumor(OSA)
56
APC based cancer vaccine
isolate monocytes → change to immature DC cells in lab → then give them specific antigenic payload activated antigen specific DC are put back into body to cause immune response sipulenucel (for prostate cancer)
57
adoptive T cell therapy
ACT bypassing the need for vaccine- trying to generate activated T cells outside body and then put back into body Large numbers of autologous anti-tumor lymphocytes are generated ex vivo • Uses T cells that recognize tumor antigens (e.g. Tumor Infiltrating Lymphocytes (TILs)) or genetically engineered T cells • Pre-conditioning regimes “prepare” the patient for adoptive transfer • “Living therapy” – administered cells survive, proliferate and kill tumor cells
58
ACT use T cells that recognize tumor antigens (\_\_\_\_) or \_\_\_
tumor infiltrating lymphocytes (TILs) genetically engineered T cells take T cells out, mature them then put them back, will kill cells and multiply (living therapy)
59
ATC using TILS
**take out tumor** **isolate T cells inside that are specific for tumor, grow them then put them back in** Non-myeloablative therapy (or TBI) prior to adoptive transfer improves the degree and duration of the response \<80% of circulating CD8+ T cells are specific for tumor in some cases TIL success is mostly limited to malignant melanoma patients (+/- lung and bladder) –tumors with high mutational load
60
CARs
ACT with genetically engineered T cells take out T cells, change them by adding chimeric antigen receptors and tumor specific TCR (adds antibody vs normal T cell receptor) then putting them back into person
61
why use antibody on T cell rather then normal receptor
cancer cells will change their MHC complexes, normal T cells can't see antibody will be able to see mutated cancer cell don't need MHC or costimulatory molecule on cancer cells
62
Defects in APC function in cancer
Mutations in MHC I and down regulation of TAP and ERp57 reduce surface expression of peptide loaded MHC-I Tumor derived IL-6, IL-10 and VEGF inhibit IL-12 production and decrease expression of MHCII-peptide, co-stimulatory molecules and LN homing molecules on APCs IL-6 and IL-10 suppress DC maturation and promote DC dysfunction Tumors promote production of TGF-β, IDO and galectin-1 by DCs which promotes a tolerogenic phenotype and Treg generation Malignant B cells have defects in MHCII expression
63
problems with CAR T cell
SEVERE ON-TARGET, OFF-TUMOR SIDE EFFECTS ELIMINATION OF “NORMAL” CELLS EXPRESSING TARGETED ANTIGEN CYTOKINE STORMS AND MACROPHAGE ACTIVATION SYNDROME
64
3 ways monoclonal antibody therapy can work
65
PDL1
T cell will attack tumor, tumor will produce PDL1 which will turn off T cell we can use anti PD1, anti PDL1 and anti CTLA4 to turn off tumor stop signal and allow Tumor specific T cells to work again
66
what therapies work at the 7 stages of tumor cycle
67
immune suppressive networks in the TME

22 spring: immunology (23 decks)

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