Tumour immune surveillance

• Tumour immune surveillance


  Monitoring and response of the immune system to detect and eliminate cancer cells

  
• Tumour immune surveillance


  • Genetic changes in cancer cells allow the immune system to recognize them as non-self
  • Immune system can also respond to stressed cancer cells
  • Cancer cells can evade immune surveillance by suppressing inflammation

  
• Several breakthroughs in clinical treatments for cancer immunotherapy:

  
• Checkpoint blockade inhibitors


  • Overcome cancer-induced immunosuppression
  • Target molecules like CTLA4 and PD1 that inhibit T cell activation and function

  
• Adoptive T cell therapy (ACT)

  • Extraction of tumour-infiltrating lymphocytes (TILs) from patient
  • Coupling of drug to TILs so they can target cancer cells
  • Reinfusion of modified TILs into patient

  
• Adoptive T cell therapy (ACT) regime

  1. Obtain tumour-specific TCR or engineer CAR T cells

  2. Expand and activate T cells ex vivo

  3. Infuse T cells into patient

  
• Tumour blood vessels


  Dysfunctional, immature vessels limit T cell infiltration into solid tumours

  
• Strategies to improve ACT efficacy


  • Enhance T cell homing and infiltration into tumours (e.g. via L-selectin engineering)
  • Overcome stromal barriers in tumour microenvironment (e.g. LRG1 blockade)
  • Promote vascular normalization to improve T cell recruitment

  
• 1. selectin enhanced T cells show improved homing, activation, proliferation, retention and persistence in solid tumours
• 1. selectin enhanced T cells synergize with checkpoint inhibitors
• Strategies to overcome immunotherapeutic challenges

  • Enhance CART cell homing and activation in tumour microenvironment
  • Match CART cell chemokine receptors to tumour microenvironment
  • Ensure sufficient CART cell numbers
  • Promote tumour blood vessel normalization
  • Induce high endothelial venule (HEV) neogenesis
  • Modify tumour microenvironment (e.g. via oncolytic viruses)

  
• Tumour infiltrating lymphocytes (TILs)


  T cells that have infiltrated into the tumour

  
• High numbers of TILs are associated with better patient outcomes in colorectal cancer

  
• T cells in colorectal tumours are not activated, leading to lack of tumour cell lysis
• Cancer immunity cycle


  The process by which the immune system recognizes, responds to, and controls cancer growth

  
• 3 E's of cancer immunoediting

  • Elimination
  • Equilibrium
  • Escape

  
• Checkpoint blockade inhibitors are more effective in cancers with high mutational load and neoantigens

  
• Microsatellite-unstable colorectal cancers have increased neoantigen-specific T cell responses and show improved outcomes with anti-PD1 therapy

  
• CART 19 T cell therapy


  Using patient's own T cells engineered to express chimeric antigen receptor CAR for CD19 on B cells

  
• CART 19 T cell therapy


  1. Taking patient's T cell

  2. Engineering them with a chimeric antigen receptor CAR

  3. A cancer specific receptor

  
• CART 19 T cell therapy

  • Approved for some leukaemias- blood cancers and lymphomas
  • Mostly successful for blood cancers as both CART cells and cancer in the same compartment- the blood

  
• CART 19 T cell therapy and other therapies aim to overcome cancer induced immunosuppression

  
• Therapies in development


  • Other checkpoint blockade inhibitors
  • Immune stimulatory pathways
  • Bispecific antibodies (anti-CD3/anti- tumour associated antigen)
  • Other T cells therapies (e.g. TILs, engineered 'natural' T cell receptors

  
• Tumour infiltrating lymphocytes (TILs)


  Lymphocytes that have infiltrated into the tumour

  
• Peritumoral lymph node-like structures


  Lymph node-like structures that develop around the tumour

  
• Tumour immune surveillance


  The immune system's ability to recognise and control the growth of cancers

  
• Low TIL density decreases the chance of patient survival
• Retrospective analysis of the density, type and location of TILs in resected primary cancers correlates with patient outcome

  
• CD8 killer T cells

  • IFN-ɣ+ Tbet+ inside and at invasive margin

  
• 1. cells have X-ray vision - they can see inside the cell
• Tumour immune surveillance


  1. T-cells recognise short peptides in complex with self-Major Histocompatibility Complex

  2. Peptides are derived from cellular proteins cleaved in the proteasome

  3. Peptides are transported, via TAP, to the ER and combine with MHC

  4. pMHCs are transported to the cell surface for scanning by the T Cell antigen Receptor

  
• Checkpoint inhibitors work at step 6-7 of the cancer immunity cycle

  
• Priming of CD8+ T cells in cancer-draining or sentinel lymph nodes


  1. Antigen presentation occurs and activate T cell

  2. Activated T cells gets to cancer

  
• Key events in T cell homing

  • T cells carried in blood at fast rate
  • Thru adhesive interactions to the endothelial cell
  • Thru low affinity selective interactions
  • Rolling receptor- Selectins
  • Activation receptor- Chemokines
  • Arrest receptor-Integrins
  • Activated integrins cause T cell stop and move thru the endothelial cell to the site of injury

  
• High Endothelial Venules (HEV)


  Specialised lymphocyte trafficking blood vessels in lymph nodes
• Lymphocyte rolling in HEV and inflamed blood vessels

  • Naïve T-cells
  • Tcm, Tscm
  • CD4 Teff
  • CTLs/CD8 Teff

  
• Homing addresses on blood vessels

  • Lymph nodes; TLS
  • Inflamed organs (skin, lungs, kidney, brain, peritoneum)
  • Cancers (inflamed, T cell rich)

  
• Inhibitory Receptor (iR)


  Expressed on T cells at different stages of an immune response
• Inhibitor Receptor Ligand (iRL)

  Expressed on APC or target cells (virus-infected cells, cancer cells)
• Exhausted T cell


  Have the right equipment to kill but whole process is held in check by the checkpoint blockade inhibitors