16. Tumour Microenvironment

• parenchyma = tissues that confer function

  stroma = everything else
• parenchyma in tumours is formed of the malignant cells, while stroma is the non-malignant supporting cells that are essential for growth
• cancers can be associated with inflammation e.g., barretts metaplasia and h.pylori leading to cancer
• seed and soil hypothesis:

  • certain cancers metastasise to particular organs due to favourable reactions between tumour cells and organ microenvironment
  • secreted factors from the primary tumour may also influence the target organ
• interstitial fluid pressure is higher in tumours due to vascular abnormalities and defects in the lymph system

  • reduces drug concentrations in tumours
• high MMPs often correlate with a more invasive phenotype
• cancer associated fibroblasts produce factors that promote angiogenesis and attract pro-inflammatory cells like macrophages (stimulate cancer cell invasion)
• infiltrate excluded tumours = immune cells trapped at tumour:stroma surface

  • respond poorly to immunotherapies
• infiltrated-inflamed tumours = hot tumours, adaptive anti-tumour mechanisms may be overcome

  • can potentially elimiate tumour
• infiltrated-tertiary lymphoid structures = lymphoid structures present at invasive margin of tumour may suggest ongoing immune priming

  • better prognosis
• tumour associated macrophages are M2 like

  • immunosuppressive
  • promote treg formation
  • poorer prognosis
  • angiogenesis promotion
  • promote metastasis
• myeloid derived suppressor cells

  • induce by inflammation
  • inhibit NK and DC function
  • induce tregs
  • deplete arginase - interfering with t cell function
• natural killer cells

  • tumour cells downregulate MHC, so should be targets of NKs
  • intratumoural NKs are often anergic so can't kill targets
  • caused by TF=GF-beta released from tumour cells
• high levels of CD8+ or TH1 t cells increase prognosis
• cd4+ TH1 cells can activate macrophages and kill tumour cells
• cd4+ TH2 t cells are thought to be a poor prognostic indicator
• tregs correlate with poorer prognosis
• hypoxia can increase CCL22, and tumour produce this

  • attracts tregs
• tregs express CD25, so starve effector T cells of IL2
• low levels of arginine leads to decreased t cell receptor signalling in t cells