Inflammation and cancer:biology to targeted therapies

Inflammation and cancer:biology to targeted therapies

Inflammation: cancer initiation:

  • Chronic inflammation initiates tumour formation and creates genetic instability which leads to more mutations
  • Inflammation and a single mutation is sufficient to drive tumour promotion

Tumour microenvironment:

  • Necrotic cells are Dead cells
  • Hypoxia is reduced oxygenation
    • Immature blood vessels in tumour are prone to collapse
    • When collapse tumour cells surrounding blood vessels will no longer be supplied with oxygen
    • Tumour cell growth can outstrip blood supply causing hypoxia as blood is only supplied to cell which is close to blood vessel
    • Hypoxia causes cells to switch on cytokines that cause angiogenesis
  • Lymphatic vessels and blood vessels are routes in which a tumour cell can spread and travel to another environment in the body
  • Contributors to tumour microenvironment:
    • Cancer cells
    • Endothelial cells
    • Fibroblasts
    • Immune cells
    • Secreted soluble growth factors
    • Extra-cellular matrix
    • Physiological and mechanical stress

How hypoxia can benefit tumour growth:

  • When oxygen concentration decline in tumours leads to hypoxia- directed secretion of cytokines and chemokines which recruit tumour promoting immune cells and supress antitumor immune responses

Immune surveillance:

  • When tumours die they release antigens
  • These antigens are then presented on surface of cancer cells
  • T-cells are primed and activated
  • T- cells migrate to site of tumour through blood vessels
  • T cells then infiltrate tumour and recognise can cells
  • After cancer cells recognised they are killed by T cells
  • Repression of autoimmunity enables cancer cell progression

Harnessing immune system to treat cancer - immunotherapy:

  • Tumours aim to reprogram immune cells to become pro-tumorigenic
  • Inhibiting pro-tumour inflammation:
    • Identify key targets which produce immunosuppressive molecules
    • Block cancer signalling pathways which drive pro-tumour inflammation
    • Targeting STAT3 aims to prevent changes in cancer and immune cells which result in immuno-suppressive tumour microenvironment
  • Promoting anti-tumour inflammation
  • PD1 receptor is expressed on surface of activated T-cells
  • Ligand (PD-L1) is expressed on dendritic cells or macrophages
  • They are co-inhibitory immune checkpoint proteins
  • Cancer cells express PD-L1 to evade the immune response
  • Radio + chemotherapy lead to upregulated PDL-1 expression
  • PD1 + PD-L1 can be targeted using immune checkpoint inhibitors
  • Checkpoint inhibitor blocks the inhibition effect causing the T-cell to be switched on as recognising antigen on tumour cell which results in lysis of the tumour cell