Introduction to TME

• Describe the proportion of cancerous cells and stromal cells within the tumour

  In most solid tumours between 35-65% of the tumour is made up of non-cancer cells. However, in some cases, such as in pancreatic cancer, non-cancer cells can make up to 90% of tumour mass.
• Describe the theory behind cancer vaccines

  Irradiated cancer cells have been injected into mice in order to sensitive the immune system to that cancer. However, the same mice will not be able to recognise other cancers. Personalised cancer vaccines can use:

  • Neoantigens: proteins that have been changed in a tumour
  • Adjuvants: stimulate the immune system
  • Modified tumour cells: causes them to express an antigen which can be recognised by TCRs
• How do cancer cells alter gene expression in order to evade antigen recognition?

  • Downregulate MHCI to avoid TCR recognition.
  • However, MHCI acts as a inhibitory ligand for NK cells, therefore downregulation of MHCI increases recognition by NK cells
  • Downregulate activating ligands such as alarm proteins, which signal cell stress:
  • MICA and MICB family: expressed on stressed or damaged cells
  • Upregulate inhibitory ligands, such as PDL1, which dampens the interaction between tumour cell MHCI molecules and TCRs
• Describe the normal action of MICA and MICB family

  • Healthy cell: MICA and MICB face the cytosolic face of the plasma membrane
  • Stressed cell: damage induces flipping of MICA and MICB to face the extracellular face of the plasma membrane to be recognised by activating receptors on NK cells
• Describe the action of M1 macrophages

  These are anti-tumour macrophages

  • Secrete inflammatory cytokines, such as IL-1 and TNF-alpha
  • Secrete chemokines
  • Produce ROS and nitrogen species
  • Secrete MMPs, such as MMP 7, 9 and 12

  M1 macrophages induce tumour cell lysis and are stimulated by LPS and IFN-gamma.
• Describe the action of M2 macrophages

  These are pro-tumour macrophages

  • Secrete pro-angiogenic cytokines
  • Secrete cytokines, which can act as mitogens and possess anti-inflammatory properties

  These macrophages are usually involved in tissue repair following resolution of infection and are less aggressive than M1 macrophages. They are stimulated by IL-10, IL-4 and TGF-beta.
• Outline pro-tumour ligands

  TGF-beta: induces immune suppression

  EGF: stimulates cancer cell growth by stimulating RTKs

  VEGF and IL-8: induce angiogenesis
• Outline anti-tumour ligands

  TNF-alpha and IFN: induce immune activation

  ROS and TNF-alpha: induce cancer cell death
• How do cancer cells manipulate the immune system?

  Cancer cells secrete specific cytokines and molecules in order to stimulate a shift from tumour suppressor cells to tumour progressive cells. However, some inflammation is required for cancer development, because without inflammation tumour cells wouldn’t be able to co-opt their microenvironment and reprogram inflammatory cells.
• Outline some examples of tumour supportive and suppressor cells

  Tumour supportive cells:

  • Tumour associated macrophages
  • Myeloid derived suppressor cells
  • Tumour infiltrating dendritic cells

  Tumour suppressor cells:

  • T cells
  • Dendritic cells
  • M1 macrophages
  • NK cells
• Describe the 4 different pathways of NK cell-mediated cell death

  Perforin Granzyme Pathway: perforin creates pores in target cell’s membrane and granzymes enter and trigger apoptosis.

  Fas pathway: NK cells express FasL, which can bind to Fas receptors on target cell and initiating apoptosis.

  TRAIL pathway: NK cells can secrete TNF-related apoptosis inducing ligand (TRAIL), which binds to death receptors and induces apoptosis

  Antibody dependent cell mediated cytotoxicity: NK cells express Fc receptors, which can bind to Fc portion on antibodies bound to tumour cells and induce apoptosis
• Describe the action of the Treg cells

  Macrophages secrete TGF-beta, which stimulates Treg cells. Treg cells then secrete IL-22, which dampens and inhibits CD4 and CD8 T cells. This creates an immunosuppressive environment for tumour growth. The higher the number of Treg cells, the greater the incidence of fatality.
• Describe alternative mechanisms to avoid surveillance

  • Inactivate immunocytes:
  • saturate immunocyte receptors with adenosine and MICA
  • release soluble FasL to induce immunoocyte apoptosis
  • Avoid apoptosis:
  • Overexpress Bcl2