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BIOL3043 - Cellular and molecular pathology > Lectures 11&12 - The Tumour microenvironment > Flashcards

Lectures 11&12 - The Tumour microenvironment Flashcards

1
Q

What is intracellular communication driven by

A

complex and dynamic network of cytokines, chemokines, growth factors and inflammatory and matric remodeling enzymes (autocrine, paracrine, juxtacrine (cell contact), endocrine)

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2
Q

The evolution, structure and activities in the cells in the TME have many parallels with what?

A

wound healing

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3
Q

What are CAFs?

A

Cancer associated fibroblasts

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4
Q

What are TILs?

A

Tumour infiltrating lymphocytes

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5
Q

What do the different levels of CAFs and TILs mean for survival rate

A

% of survival decreases as CAFs increase and TILs decrease

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6
Q

What do lots of fibroblasts infer about cancer prognosis

A

Bad prognosis

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7
Q

What do lots of CD8 cells infer about cancer prognosis

A

Good prognosis

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8
Q

What are the major types of cells in the TME

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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9
Q

What is a fibroblast

A

Ubiquitous cell - most common cell of connective tissue

Typically mesenchymal origin

Structural cell – maintain structural integrity of connective tissue

Produce extracellular matrix - collagen, glycosaminoglycans, reticular & elastin fibres

Involved in organ homeostasis – inflammation (switch on and off) , wound healing and fibrosis – produce scar tissue

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10
Q

Explain fibroblasts role in inflammation

A

Can be present as specialised types of fibroblasts

Can also be present in non-lymphoid tissue

Also involved on switching inflammation off once wound has healed

Produce cytokines ans chemokines

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11
Q

What are some cytokines and chemokines fibroblasts produce?

A

Cytokines - TGFβ1, IL1β, IL6, IL33

Chemokines - CXCL12, CXCL13, CCL2,

ECM proteins – collagens, fibronectin, tenascin

In cancer- they protect cancer from the immune system

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12
Q

What does a fibroblast become when its activated

A

Myofibroblast

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13
Q

Explain the process of a fibroblast turning into a myofibroblast

A

Fibroblast encounters mechanical stress -> turns into a proto-myofibroblast with focal adhesions and Filamentous actin

proto-myofibroblast encounters mechanical strss cytokines e.g. TGF-b -> tuns into myofibroblast with FAs, Filamentous actin and a-SMA

Both proto-myofibroblasts and myofibroblasts have ED-A fibronectin (Fibroblasts have fibronectin only)

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14
Q

What are myofibroblasts

A

Typically ‘activated’ through TGF-beta signaling (also need tissue tension/mechanical stress)

Contractile, secretory cells that produce ECM

Function to contract a wound and produce scar tissue (resolve the wound)

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15
Q

how can you test for the upregulation of collagen in fibroblasts with TGF-b added

A

Gel contraction assay

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16
Q

What are some features of CAFs

A

A fibroblast in a cancer

The major stromal type in most solid cancers

Historically, the term cancer associated fibroblast has referred to cells resembling ‘activated’ myofibroblasts as found in wound healing

Contractile cells expressing α-smooth muscle actin (SMA) stress fibres

Generated through TGF-β1 signalling

Produce and secrete large amounts of ECM proteins

Secrete growth factors and cytokines

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17
Q

True or false: CAF are plastic cell type population and can change phenotype

A

TRUE

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18
Q

Why do fibroblasts change phenotype

A

Don’t want fibroblasts to keep producing ECM once wound has healed

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19
Q

Explain the different CAFs in cancer

A

myCAFs : tend to work through justocrine interactions, so would ususially find myCAF cell lying up against the tumour as ist cell-cell interactions that the myCAF is communicating through

Also a population of iCAFs - inflammatory CAFs : usually found further from the tumour cell, they have secreting factors such as IL-6/IL-11, there are then having an effect on the tumor cells (not the iCAF itself – paracrine)

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20
Q

Explain the triggers for Quiescent plutipotent stem cells to turn into myCAFs and iCAFs

A

myCAF – TGF-β, blocks IL-1 signaling (immunosuppressive)

ICAF – NF-kB signaling and JAK/STAT signaling (promoting immune system)

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21
Q

What are myofibroblastic CAFs associated with

A

aggressive cancers and poor prognosis, they promote metastiasis

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22
Q

Often when there’s many CAFs there will be little…

A

T cells (due to immune suppression)

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23
Q

What does the ECM consist of

A

fibronectin, collagens, periostin, tenascin, proteoglycans, MMPs

24
Q

What are Haematogenous vs Lymphatic metasiasis

A

Metastasis – No longer connected to surface epithelium, spread of tumour to distant organs

 Haematogenous – via bloodstream 

 Lymphatic – to lymph nodes
25
Q

What does Transcoelomic mean in terms of cancer spread

A

across body cavities

26
Q

What does Implantation/transplantation mean in terms of cancer spread

A

normally due to tumour gets accidentally inserted to somewhere else by a surgeon (rare)

27
Q

What percentage of cells entering circulation develop into metastasis?

A

<0.01%

28
Q

How do CAFs promote invasion and metastasis

A

Secretion of cytokines (TGF-β1, 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

29
Q

How can tumour invasion be studied in the lab?

A

Plating tumour ells onto gels containing fibroblasts - feed with medium and at end and take gel and process it and take sections - can see in cancer surface epethilum and island of tumour cells invading

30
Q

How can metastasis be studied in the lab?

A

4T1 grows in immunocompetent mice

Can co-inject tumour cells with finroblasts or CAFs

When we do this we can see in the primary tumours when we stain for smooth muscle actin, can see SMA positive stroma, also tumours grow much bigger, much quicker

31
Q

What does CAF promote in the lungs

A

Metastatic deposits

32
Q

What do high T cell levels infer about cancer survival?

A

Better survival chance

33
Q

Explain the process of immunoediting, three Es: elimination, equilibrium and escape

A

Elimination - any potential cancer cells are eliminated, immunosurveillance and adaptive and innate immunity active

Equilibrium - persistance, genetic instability and immunoselection. mmune system no longer able tp kill off tumour cells, but the tumour is not getting any larger

escape - progression, chronic inflammation and cancer progression

34
Q

What specific T cell type is associated with better survival?

A

CD8 T cells

35
Q

What do Tumour-infiltrating lymophocytes (TILs) recognise?

A

Viral antigens in HPV+ in oropharyngeal cancer

36
Q

What is oropharyngeal cancer

A

Cancer of the head and neck, caused by smoking and drinking, can also be caused by HPV virus

37
Q

Is surival higher in people with HPV causing head and neck cancer, or HPV -ve

A

Survival higher in HPV causing cancer (T cells recognise virus specific antigens)

38
Q

Compare the transcriptomics of HPV+ and HPV-ve oropharyngeal cancer

A

Transcriptomics are different

In HPV+ there were lots of immune genes that were unregulated

Looking at T cell levels in HPV+ cancers - much higher levels

About 15% of HPV+ don’t have high levels of T cells and their prognosis was much poorer

39
Q

How do CAF promote tumour immune evasion?

A

No one single mechanism responsible: lots of things that inhibit its of types of immune cells

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

40
Q

Explain how cytotoxic (CD8) T-lymphocytes are tumour killer cells

A

Focus on these as these are the soldiersof the imune system

Recognise specific antigens bound to Class I MHC

Activation requires 2 signals - TCR (T-cell) & antigen-bound MHC Class I (APC)

  -Costimulation CD28 (T-cell)  by CD80/86 (APC)

Expansion – IL-2

Express perforin, granzyme, Granulysin, FasL

41
Q

What are the tumour antigens?

A

Mutated proteins - neoantigens

Oncofetal antigens – eg CEA

Testis antigens – eg MAGE

Highly overexpressed antigens – eg tyrosinase

Viral antigens – eg HPV

42
Q

Describe immune hot vs immune cold tumours

A

Immune hot – got lots of T cells within them

Immune cold – 2 different patterns

Excluded – CD8T cells stuck around edge of tumour and can’t get at tumour cells

Desert – doesn’t seem to be an immune response at all

43
Q

Whats a proposed way that immune therapy could work more effectively to treat cancer

A

The T cells are there and want to try destroy the tumour, so If you could get a drug for eg, and it could get T cells into the tumour – perhaps that would be a way of getting immune therapy to work more effectivly

44
Q

Explain the dysfunction of CD8-T cells in tumours

A

Immunosuppressive immune infiltrate and tumour cells – Tregs, MDSCs, TAMs, TANs etc.

Hostile environment – hypotoxic, acidic, nutrient depleted, toxic metabolites

Suppressive receptors – PD-L1/L2, VISTA etc.

Inhibitory enzymes – Arginase, IDO-1

Lack of Co-stimulation – T cell intrinsic dysfunction, PD-1, LAG-3, Tim-3 etc.

Upregulation and suppressive signaling : Suppressive molecules – IL-10, TGFβ, adenosine, PGE2

45
Q

Describe the regulation of T cells through different receptors present on them

A

Activating:
CD28, OX40, CD40, CD27

Inhibatory:
LAG3, PDL1, CTLA4 (PD1 and CTLA4 both have drugs that interact)

46
Q

What are the two different types of TAMs

A

M1 expressed - MHC class II, CD14, CD80 (inflammatory

M2 expressed - CD36, CD163 anti-inflammatory - promote angiogenesis

Now been seen that these two categories not totally correct as seen to be mixed expression

47
Q

What analysis is carried out to ensure precision medicine is precise

A

‘omic’ analysis - but sequencmg DNA by itself doesnt give you that much useful info

analysis expensive - if a pathology test could be created would be much cheaper

48
Q

What happens if you group data according to DNA mutations

A

no pattern, messy, however if you look at gene expression pattern, subgroups start to appear

49
Q

How is it decided who gets immunotherapy treatment

A

stain cancer for PD-L1
scoring system, if scoring is high enough, patient is eligible for anti-PD-L1 treatment

Problem:
- many pharmaceutical companies have developed drugs against PD1, so systems have become very complex
- test not hugely accurate of predictive, patients who test negative for this can still benefit from drug
- PDL1 expression is heterogenous

50
Q

Explain why higher mutation rates lead to better immunotherapy response

A

Immunotherapy uses mechanism of recognising tumour as non-self, so higher the mutations, more likely it is to express mutated MHC I antigens

51
Q

Explain what studies showed about patients who don’t respond well to immunotherapy

A

patients with high levels of fibroblasts (CAFs) in tumours tend to be associated with non-response, therefore this is a target area for getting immunotherapy to work better

52
Q

What are the 4 subtypes of the pan-cancer microenvironment, which one is associated with immunotherapy resistance

A

immune-enriched, fibrotic

immune enriched, non-fibrotic

fibrotic

depelted

immunotherapy resistance - fibrotic (Bagaev 2021)

53
Q

How could you target a CAF

A

‘Normalise’ CAF - TGFb inhibition, NOX4 inhibition

Kill CAF population - CAF directed vaccination

Block CAF function - target CXCl12

54
Q

How could you target a CAF

A

‘Normalise’ CAF - TGFb inhibition, NOX4 inhibition

Kill CAF population - CAF directed vaccination

Block CAF function - target CXCl12

55
Q

What would be the problem with blocking TGFb to target CAFs

A

TGFb involved in tissue homeostasis and in early stages of cancer development TGFb helps supress cancer development

small molecules developed showed cardiac toxicities

56
Q

What are ways of localising inhibition of TGFb

A
  • neutralising antibodies
  • small molecule inhibators
57
Q

Whats a another way that CAF is regulated

A

NOX4 - enzyme that produces ROS

can block NOX4 - CAF goes from myofibroblatoc phenotype to normal quiescent like cell

(tested with SMA staning)

tumours grew much smaller and CD8T cells infiltate

BIOL3043 - Cellular and molecular pathology (11 decks)

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