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Cellular & Molecular Pathology > The tumour microenvironment > Flashcards

The tumour microenvironment Flashcards

1
Q

non tumor cells can make up what percentage of a tumor

A

> 50%

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2
Q

what sort of intracellular communication molecules are involved in tumours

A

complex and dynamic network of cytokines, chemokines, growth factors and inflammatory and matrix remodeling enzymes

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3
Q

__ levels of Cancer assocaited fibroblasts = better chance of survival

A

Low levels of cancer associated fibroblasts = better chance of survival

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4
Q

__ levels of tumour infiltrating lymphocytes = better chance of survival

A

high levels of tumour infiltrating lymphocytes = better chance of survival

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5
Q

what four molecular classifications can tumours be put into?

A
  • Immune enriched, non-fibrotic
  • Immune enriched, Fibrotic
  • Fibrotic
  • Desert
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6
Q

what are the major cell types in the tumor microenvironment

A
  • Cancer-associated fibroblasts
  • Adipocytes
  • Cells of the vasculature
    Vascular endothelial cells
    Pericytes
  • Immune cells
    Tumour-associated macrophages
    T lymphocytes – eg CD8+, CD4+, CD4/FoxP3+
    B lymphocytes
    Natural Killer cells and Natural Killer T cells
    Dendritic cells
    Myeloid-derived suppressor cells
    Tumour-associated neutrophils
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7
Q

what is a fibroblast?

6 points

A
  • non-hematopoietic, non-endothelial, non-parenchymal, non-epithelial, non-mesothelial cells (Look for Spindle shaped cell with absence of all these cell types)
  • Ubiquitous cell - most common cell of connective tissue
  • Typically mesenchymal origin – expresses vimentin (note that fibroblasts from different anatomical sites have differing developmental origins)
  • Structural cell – maintain structural integrity of connective tissue
  • Produce extracellular matrix - collagen, glycosaminoglycans, reticular & elastin fibres
  • Involved in organ homeostasis – inflammation, wound healing and fibrosis
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8
Q

describe the 3 roles of fibroblasts in secondary lymphoid organs in the regulation of inflammation

A

setup: release of chemokines CCL21 & CCL19 to localise and recruit dendritic cells and naive t cells
support: fibroblast reticular cell relaxation and LN swelling to cause t cell clonal proliferation
suppress: release of NOS2 to decrease proliferation of activated t cells

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9
Q

describe the 3 roles of fibroblasts in non lymphoid tissues in the regulation of inflammation

A

setup: release of chemokine CXCL13 for the localisation and recruitment of peritoneal B cells
support: by stimulation of cytokines TNFalpha, IL-1beta and LPS they release CCL2 and IL8 to increase recruitment of neutrophils and monocytes
suppress: release of IL-33 to stimulate T reg cells to increase tissue homeostasis

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10
Q

describe the role of fibroblasts in wound healing

A

fibroblasts activate into myofibroblasts after mechanical stress and TGFbeta singalling.
myofibroblasts express alpha-smooth muscle actin (SMA) stress fibre wchic function to contracct a wound and produce scar tissue

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11
Q

what is a cancer associated fibroblast?

A

a fibroblast in cancer - contractile cell.s expressing smooth muscle actin (SMA) stress fibres generated through TGFbeta1 signalling that produce and secrete large amounts of ECM proteins and growth factors and cytokines
the major stromal type in most solid cancer

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12
Q

what two major phenotypes can CAFs switch between

A

Myofibroblastic CAFs
Inflammatory CAFS

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13
Q

what are the major differences between mCAFs and iCAFs

A

mCAFs -
iCAFs - more distant, promote inflammation, release IL1alpha inducing JAK/STAT signalling

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14
Q

give four ways a cancer can travel around the body

A

Haematogenous – via bloodstream
Lymphatic – to lymph system
Transcoelomic – across body cavities
Implantation/transplantation -operative error, accidental implantation by a surgeon

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15
Q

brain metastasis sees commonality with what other cancer types

A

Lung
breast
melanoma
renal cell
colorectal

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16
Q

lung metastasis more commonly leads to what cancer types

A

renal cell
colorectal
melanoma
breast
sarcoma

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17
Q

liver cancer often metastasises to what types of cancer

A

colorectal
pancreatic
breast
lung
stomach

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18
Q

bone metastasis sees commonality with what other types of cancer

A

breast
lung
prostate
renal
colorectal

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19
Q

how do CAF promote invasion and metastasis?

4

A
  • Secretion of cytokines (TGF-b1, HGF, CXCL12) – induction of tumour cell EMT
  • Secretion of ECM (collagens, cross-linking collagen [LOX enzymes]) – increasing tissue stiffness and activatIng tumour cell mechanotransduction signaling pathways
  • Remodeling ECM (secreting enzymes such as matrix metalloproteinases [MMPs] – creating tracks for tumour cells
  • Secretion of other factors – IL6, 1L32
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20
Q

what are the three stages of immunoediting?

A

elimination - immunosurveillance, innate and adaptive immunity
equilibrium - persistance, genetic instability and immunoselection
escape - progression, chronic inflammation

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21
Q

why are cancers caused by viruses associated wiht a better chance of survival than those with smoking

A

because T cells find it easy to identify tumours caused by a virus because they express viral specific antigens
in addition lots of immune related genes are switched on in HPV+ tumours

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22
Q

how do CAFs promotes tumour evasion?

A
  • Inhibit CD8 T-cells
  • Exclude CD8 T-cells
  • Kill CD8 T-cells
  • Inhibit dendritic cells
  • Inhibit NK cells
  • Promote suppressive T-regs
  • Promote MDSCs
  • Promote M2 macrophages
23
Q

cytotoxic CD8 t lymphocyte activation requires what two signals

A
  1. TCR (T-cell) & antigen-bound MHC Class I (APC)
  2. Costimulation CD28 (T-cell) & CD80/86 (APC)
24
Q

what cytokine is needed for cytotoxic T lymphocyte expansion

A

IL2

25
Q

give five types of tumour antigens

with an example

A
  • Mutated proteins - neoantigens
  • Oncofetal antigens – eg CEA
  • Testis antigens – eg MAGE
  • Highly overexpressed antigens – eg tyrosinase
  • Viral antigens – eg HPV
26
Q

what are the two types of immune cold tumours

A

excluded and desert

27
Q

what causes dysfunction of CD8 T cells in tumours?

A
  • immunosuppressive immune infiltrate and tumour cells (Treg, MDSCs, TAMs, TANs etc)
  • suppressive molecules (IL10, TGFbeta, adenosine, PGE2 etc)
  • lack of co-stimulation (PD1, LAG3, Tim3)
  • aberrant tumour vasculature (adhesion molecule downregulation, FasL upregulation, inhibitory receptors and secreted molecules)
  • mismatched chemokine network (ones that attract immunosuppressive infiltrate and not t cells)
  • pMHC downregulation (genetic or epigenetic)
  • inhibitory enzymes (arginase 1, IDO1)
  • suppressive receptors (PD-L1/L2, VISTA)
  • hostile environment (hypoxic, acidic, nutrient depleted, toxic metabolites)
28
Q

what are the major effects of CAF on CD8 T cells?

A
  • Exclusion of CD8 T-cells from tumours – secretion of CXCL12, TGFb, ECM proteins
  • Killing of CD8 T-cells – expression of FASL and PDL2
  • Suppression of CD8 activation and proliferation
    o Expression of CD39 and CD73
    o Expression of CXCL5/1L6
  • Interfering with antigen presentation and activation
29
Q

what are t regulatory cells

what induces and expands them?

A

A subset of CD4+ T-cells (FoxP3+) that act to suppress the immune response (maintain tolerance to self antigen)
* Immunosuppressive – suppress induction and proliferation of cytotoxic T-cells
* Induction and expansion can be induced by TGF-b1
* Produce TGF-b1

30
Q

what is the master immune suppressor

A

TGFbeta

31
Q

what are the functions of Treg cells?

A
  • Induce apoptosis of CD8+ T-cells
  • Interact with dendritic cells – IDO, LAG3, TIGIT
  • Production of immunosuppressive adenosine
  • Prevention of co-stimulation through CD28 effector CD8+ T-cells
32
Q

what are the differences between the M1 and M2 phenotypes of professional phagocytes

A
  • M1- classical interferon activation proinflammatory and cytotoxic, secrete high IL12. Th1 reponses, kill tumour cells/ auntitumour immunity
  • M2 –alternative activation by IL4 – anti-inflammatory, promote wound healing and angiogenesis, Produce high levels of IL10 and TGF-b1. Th2 responses, tissue remodelling, angiogenesis and tumour progression
33
Q

describe the experiment that showed how CAFs help tumour

A

inject mice with a mixture or tumour cells and CAFs (CAFs dont appear wihtout injection)
when CAFs present, tumour grows faster, more macrophages are present, stop CD8 T cells getting into the tumour, no effect on CD4 T cells

34
Q

what percentage of mutaions are druggable?

A

only 10%

explains why sequencing the whole DNA by itself isnt massively useful

34
Q

what percentage of mutaions are druggable?

A

only 10%

explains why sequencing the whole DNA by itself isnt massively useful

35
Q

what percentage of mutaions are druggable?

A

only 10%

explains why sequencing the whole DNA by itself isnt massively useful

36
Q

what types of ‘omic’ sequencing analyses can be done for precision medicine

A
  • full genome sequencing (mutation and copy number)
  • metabolomics and proteomics (molecular alterations)
  • transcriptomics (miRNA epigenetics)
37
Q

how do clinics decide who receives PDL1 treatment

what are the variables and problems

A

take biopsy and stain cancer for PDL1, if scoe is high enough then the patient is eligible to get the drugs

different drugs, different PDL1 tests, different cut-offs, different cells scored

PDL1 negative patients can derive benefit, PDL1 expression in tumours is heterogenous, PDL1 can be expressed in mutiple cell types, the test for PDL1 is not hugely accurate

38
Q

can DNA mutations predict response to immunotherapy ?

A

Patients with mutations in the interferon (IFN)-γ pathway genes, IFNGR1/2, JAK1/2, and IRF1, are poorly responsive to immunotherapy
those with High mutational burden do better with immunotherapy - More mutation you have the more likely you are to have it transcribed and translated then presented on a MHC class 1 cell.

39
Q

why don’t all mutations generate antigens?

A
  • only a minority of mutations generate peptides that are properly processed and loaded on to MHC complexes
  • even fewer are able to be recognized by T cells
  • not all neopeptides presented on the cell surface are immunogenic
40
Q

why does high mutational burden relate to more neoantigens?

A

More mutation you have the more likely you are to have it transcribed and translated then presented on a MHC class 1 cell. more likely to initiate an immune response against the tumour

The more somatic mutations a tumor has, the more neoantigens it is also likely to form, and TMB can represent a useful estimation of tumor neoantigenic load

41
Q

how does TGFbeta contribute to treatment failure?

A

TGFbeta attenuates tumour response to PD-L1 blockage by contributing to exclusion of T cells
TGFbeta associated extracellular matrix genes link cancer-assiciated fibroblasts to immune evasion and immunotherapy failure

42
Q

give three strategies to target CAFs

A

‘Normalise’ CAF - inhibition of TGFbeta and NOX4, Vit D & A
Kill CAF population - target FAP expressing cells CAF directed vaccination
Block CAF function - target CXCL12/CXCR4

43
Q

what are the roles of TBFbeta in tumourigenesis?

A
  • Suppressive in the early stages of tumorigenesis
    - cell cycle arrest (P15 P21 Myc )
    - apoptosis BIM BIK DAPK
  • Tumour promoting in later stages of tumorigenesis
    - Promotes epithelial to mesenchymal transition (EMT) - invasion & metastasis , chemoresistance
    SNAIL1/2 TWIST ZEB1/2
    Tumour microenvironemnt
    - Immune evasion
    - Angiogenesis CTGF VEGF
    - activate Cancer-associated fibroblasts
44
Q

what tumour intrinsic and extrinsic factors lead to insufficient anti-tumour T cell generation

A

Tumour intrinsic – genetic & epigenetic mechanisms influencing neoantigen formation, expression and presentation. Alterations in signaling pathways that disrupt the action of cytotoxic T-cells

Tumour extrinsic – non cancerous stromal or immune cells, host microbiota etc

45
Q

what tumour intrinsic and extrinsic factors lead to inadequate anti-tumour T cell function?

A

Tumour intrinsic – Expression of inhibitory T-cell ligands eg PDL1, FasL expression etc
Tumour extrinsic – Expression of inhibitory ligands – PDL1, PDL2, FasL, inhibitory receptors on T-cells, PDL1,

46
Q

what tumour specific antigens could be possible vaccination targets?

TSA; unique to tumour cell, does not occur in normal cells

A

Viral antigens (HPV - E6, E7 & E2, E5; EBV)
Idiotype antigens B-cell tumours
New proteins or peptides (neoantigens) arising as results of mutations

47
Q

what tumour associated antigens could be potential vaccination targets?

TAA: not unique to cancer but have limited expression in normal tissues

A

Embryonal antigens alphafetoprotein, carcinoembryonic antigen
Differentiation antigens tyrosinase, gp100, melan A in melanoma
Cancer testis antigens NY-ESO, MAGE A1, 3 in many cancers

48
Q

how does TGFbeta promote a broadly suppressive microenvironment?

A
  • Suppress CD8 T-cell proliferation and cytotoxicity
  • Decrease effector function of CD4 T-cells and suppress Th1 response
  • Promote T-reg differentiation
  • Promote tolerogenic phenotype of dendritic cells – decreased maturation & antigen presentation
  • Skew macrophage to M2 phenotype and increase arginase secretion
  • Skew neutrophils to N2 phenotype
49
Q

what are the main problems with targetting TGFbeta?

A

tumour suppressive role in early stage disease
first generation small molecule inhibitors triggered on-target cardiac toxicities and promoted development of cutaneous squamous carcinomas

50
Q

give examples of stretegies for TGFbeta targeting

A
  • Suppress activation – anti-avb6/avb8, soluble LAP
  • Receptor kinase inhibitors - small molecule inhibitors (eg Galunisertib - LY2157299; Vactosertib)
  • Neutralising antibodies (eg. ID11 – anti-pan-TGFb antibody; XPA-42-089 binds TGFb1 and TGF-b2, but not TGF-b3)
  • Chimeric antibody traps (eg. CD73-TGFb; CTLA4-TGFBR2; PDL1-TGFBRII)
  • Antisense oligonucleotides (Trabedersen - TGFb2 antisense
51
Q

CAF differentiation is regulated by what

inhibition of it results in…

A

NOX4 dependent ROS

NOX4 inhibition reverses CAF differentiation and overcomes CD8 T cell exlcusion in vivo

52
Q

when immunoprofiling of tumours is carried out what cells are they assessing?

A

Assess burden and activation status
T cells
B cells
Macrophages
Other cells of interest
Other markers of interest

Cellular & Molecular Pathology (12 decks)

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