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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
Q

MDSC have Direct suppressive effect on___responses

A

NK and CTL

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26
Q

MDSC have NOS and ROS nitration of the TCR on CTLs preventing ___ interaction

A

MHC

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27
Q

In MDSC, Arginase depletes extracellular arginine, preventing___cell activation

A

CD8 and CD4 T

28
Q

Arginase helps expand ___ population

A

Treg

29
Q

M2 monocytes

A

tissue repair and angiogenesis

tumor promotion

down regulation of M1 and adaptive immunity

30
Q

TAM are type ___ and are involved in___

A

M2 monocytes

metastasis, down regulation of adaptive immunity and tumor production

31
Q

IL 10 is made by __ and does what

A
32
Q

IDO is made by ___ and does ___

A
33
Q

immune checkpoints

A

down regulate immune response after elimination of disease

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
Q

CTLA-4

A

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
Q

PD-1

A

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
Q

CTLA-4 has higher affinity for ___ interrupting activation signal, downregulating T cell function and inhibiting excessive T cell expansion

A

CD80/86,

37
Q

In the TME, tumor-specific T cells are inactivated by ___ on
the tumor cell resulting in tolerance/anergy

A

PD-L1 or PD-L2

38
Q

Cancer cells exist in a ___relationship with their local microenvironment

A

symbiotic

39
Q

The ___ is complex, and like tumor cells, evolves in response to environmental pressures

A

microenvironment

40
Q

Standard therapies do not address the___ and its contribution to oncogenesis/tumor cell survival

A

local immunosuppression

41
Q

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

A

immunosuppression

42
Q

Improved efficacy of immunotherapy will likely require combination therapies to address the __

A

TME

43
Q

The goal of cancer immunotherapy is to initiate / augment a self-propagating cycle of anti-tumor immunity that further ___ responses

A

amplifies and broadens tumor-specific T cell

44
Q

steps of cancer immunity cycle

A
45
Q

tumor associated antigens

A

found on tumor cells and normal cells

Qualitative and quantitative differences distinguish normal from abnormal

46
Q

how do autologous and allogenic whole tumor cell vaccines work

A

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
Q

peptide vaccine

A

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
Q

oncept

A

DNA vaccine for melanoma with human tyrosinase in it

49
Q

DNA vaccine

A

have plasmid (circle of DNA) codes for tumor antigen

eaten by APC and presented to cause Tumor specific T cell reaction

50
Q

explain

A

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
Q

two things that can be used as biological vector to deliver tumor associated antigen

A

Adenoviral vectors

Listeria monocytogenes based vaccines

52
Q

adenoviral vector

A

used to deliver TAA(tumor associated antigens) DNA into cell

generates cytotoxic T cell responses against TAA

eg. Telomerase

53
Q

listeria monocytogenes based vaccines

A

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
Q

MHC 1→ __

MHC 2→ ___

A

MHC 1→ CD8

MHC 2→ CD4

55
Q

canine OSA vaccine

A

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
Q

APC based cancer vaccine

A

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
Q

adoptive T cell therapy

A

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
Q

ACT use T cells that recognize tumor antigens (____) or ___

A

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
Q

ATC using TILS

A

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
Q

CARs

A

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
Q

why use antibody on T cell rather then normal receptor

A

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
Q

Defects in APC function in cancer

A

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
Q

problems with CAR T cell

A

SEVERE ON-TARGET, OFF-TUMOR SIDE EFFECTS

ELIMINATION OF “NORMAL” CELLS EXPRESSING TARGETED ANTIGEN

CYTOKINE STORMS AND MACROPHAGE ACTIVATION SYNDROME

64
Q

3 ways monoclonal antibody therapy can work

A
65
Q

PDL1

A

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
Q

what therapies work at the 7 stages of tumor cycle

A
67
Q

immune suppressive networks in the TME

A

22 spring: immunology (23 decks)

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