L15 - Intro to TME and immune system

Question 1

TME: what is it and why are investigations into it not always clear?

Answer 1

Tumour microenvironment

The TME is different in every single location and every different individual - difficult to get clear universally applicable results

Question 3

The four types of tissue

Answer 3

Epithelial Tissue - It is a protective layer that covers the body’s surface, lines internal organs, and forms glands

Connective Tissue - This tissue provides support, protection, and structure to the body. It includes bone, cartilage, blood, adipose, and fibrous tissue

Muscular Tissue - This tissue is responsible for movement and includes skeletal, smooth, and cardiac muscle

Nervous Tissue - responsible for communication between different parts of the body and includes neurons and supporting cells called glial cells

Question 4

Typical rules of cancer

Answer 4

• Cancer cells have escaped the normal limitations of external cue-driven cell division
• Have modified their local environment to exceed the naturally defined tissue borders
• Forms a multicellular mass driven by a “transformed” cancer cell
• Have mechanisms to survive immune surveillance and cell death

Question 5

Solid tumours: how much space is occupied by non-cancer cells?

Answer 5

In most solid tumours between 35-65% of the tumour is made up of non-cancer cells

In some pancreatic cancer, this can be 90% of mass

Question 6

What types of cells can be found in the TME?

Answer 6

Adaptive and immune cells are present in most cells and the mix of those cells is key to the development and treatment outcome

Question 7

TME immune system 101: why we can’t catch cancer

Answer 7

Different in each immune system - cancer will only grow in its own body?

Cancer can only avoid the body’s natural defences if it comes from its own body - it can’t thrive in another body?

> 99% of cancer cell proteins are normal

Question 8

What ways can cancer cells avoid death?

Answer 8

Downregulation of MHC class I

Question 9

Tumour supportive and tumour suppressive cells: what types are there and what do they do?

Answer 9

Tumour supportive cells:
* M2 TAM, tumour-associated macrophages
* MDSC, myeloid-derived suppressor cells
* TIDC, tumour-infiltrating dendritic cell

Tumour suppressive cells:
* T cells, T lymphocyte
* DC, dendritic cell
* M1 TAM, M1 macrophage
* NK, natural killer cell

Question 10

M1 TAM: what are they, what are they activated by, what do they do, and do they suppress or support cancer?

Answer 10

M1 Tumour-associated macrophage

LPS/IFN-γ

• Cytokines (ie immunoinflammatory ones)
• Chemokines (ie ones activating immune cells)
• Tumour cell lysis
• Activate NPS/NOS
• Activate metalloproteinase (MMP7/9/12)

Suppress

Question 11

M2 TAM: what are they, what are they activated by, what do they do, and do they suppress or support cancer?

Answer 11

M2 Tumour-associated macrophage

• Hypoxia
• TGF-β
• IL-10
• IL-4
• Cytokines (ie immunoinflammatory ones)
• Chemokines (ie ones activating immune cells)
• Tumour cell lysis
• Activate NPS/NOS
• Activate metalloproteinase (MMP7/9/12)

Suppress

Question 12

M1 TAMs: what is the normal path of tumour cell destruction?

Answer 12

• Immune activation by TNF-α, IL-23, IL-1β, CXCL10, IFN-γ, NO
• Apoptosis of cancer cells by NO, TNF-α, and ROS
• Tissue damage by ROS
• Phagocytosis of cancer cells
• Maturation of APCs by IL-12

Question 13

M2 TAMs: what is the normal path of tumour cell destruction?

Answer 13

• Immune suppression by IL-10, TGF-β, and PD1/PDL-1
• Invasion and metastasis by TGF-β
• Tissue remodelling and fibrosis by MMPs and chatepsins
• Proliferation and survival of cancer cells by EGF, FGF, and PDGF
• Angiogenesis by VEGF, FGF, and CXCL8

Question 14

Immunotherapy

Answer 14

Uses the immune system to fight cancer

Question 15

Anti-tumour microenvironment

Answer 15

• M1 macrophages
• TGF-β
• IFN-γ, activates b cells, activates CD8 with IL-2
• DC secreting IL-6 and TNF
• Neutrophils secreting ROS

Question 16

Immune-suppressive microenvironment

Answer 16

• B cells secreting TGF-β, IL-10
• Tregs
• M2 secreting IL-4
• Tumour releasing VEGF
• Tregs secreting IL-2? suppressing NK cells?

Question 17

Do T-cells and NK cells have the same activation pathway?

Answer 17

The MHC signal is the opposite in NK cells compared to T cells

Whatever that means (leccy it up)

Question 18

NK cells: what pathways can they use to destroy cells?

Answer 18

Perforin/granzyme pathway - creates pores in the target cell’s membrane, allowing granzymes to enter and trigger apoptosis

Fas/FasL pathway - NK cells Fas ligand (FasL) on their surface binds to Fas receptors on the surface of target cells, leading to the activation of caspases and apoptosis

TRAIL pathway - TNF-related apoptosis-inducing ligand binds to death receptors on the target cell surface, causing caspases and apoptosis

Antibody-dependent cell-mediated cytotoxicity (ADCC) - NK cells express Fc receptors on their surface that can bind to the Fc portion of antibodies already bound to tumour cells, leading to granzyme release and apoptosis

Question 19

Tregs and CD8 cells: what do they do and what happens if either are too present int he ECM?

Answer 19

• Tregs control the immune response and prevent overactivation of the immune system
• CD8 cells destroy cells and prevent the survival of unneeded cells

If Tregs are too present, cancer is supported as the immune system is downregulated and cancer can thrive
If CD8 cells are too present autoimmunity is supported as the cytotoxic cells attack the body

Question 19

How does the TME favour Tregs?

Answer 19

leccy it up

Question 19

How do immune cells avoid surveillance?

Answer 19

• Suppress MHC expression - hiding antigens
• Overexpress PDL1 - inhibit T-cell/tumour checkpoint
• Overexpress BCL2 family members - avoid apoptosis
• Manipulate the balance of immune cell types using TGFbeta, IL10, tREGs, more M2 macrophages etc