Lesson 14 Mutational load and Immunotherapy

• CRICOS Provider 00115M
• MED3ATA Cancer Module

  
• Christine Hawkins
• Lecture 14.1: Avoiding Immune Destruction Hallmark: Mutational load and immune killing of cancer cells

  
• La Trobe University
• COMMONWEALTH OF AUSTRALIA Copyright Regulations 1969 WARNING This material has been reproduced and communicated to you by or on behalf of La Trobe University pursuant to PART VB of the Copyright Act 1968 (the Act). The material in this communication may be subject to copyright under the Act. Any further copying or communication of this material by you may be the subject of copyright protection under the Act. Do not remove this notice.
• Throughout these cancer lectures: Brown text is examinable, Grey text is just for your interest: not examinable
• Hanahan D, Weinberg RA. Hallmarks of cancer: the next generation. Cell. 2011;144:646-74.

  
• Hallmark 5: Avoiding immune destruction


  Cancer cells as "altered self", Mutational load, neoantigens, Activation of T cells, CTLA4 block, T cell killing, PD-1 block, Therapies: CAR T cells, Ipilimumab, Nivolumab

  
• Science can move fast!
• Hanahan D, Weinberg RA. Hallmarks of cancer: the next generation. Cell 144: 646-74, 2011

  
• Avoiding immune destruction and tumour promoting inflammation?????

  
• Many tumours contain immune cells
• This may be a sign that the immune system is "trying" to eliminate cancerous cells

  
• People/animals with weakened immune systems are prone to cancers
• Immune cells, particularly innate immune cells, can promote cancer progression by providing: inflammatory growth factors that sustain proliferative signalling, survival factors that limit cell death, proangiogenic factors, extracellular matrix-modifying enzymes that facilitate angiogenesis, invasion, metastasis, reactive oxygen species which mutate cells and can provoke additional genetic changes that can hasten cancer development

  
• Solid transplant recipients, who receive immune-suppressive treatments to prevent rejection, are 3-5 fold more likely to develop cancers than non-transplant recipients

  
• Patients with virally-impaired immune systems are prone to cancers

  
• Individuals with genetic immune deficiencies are also cancer-prone (but other factors are also implicated in this context)

  
• Cancer cells: altered-self


  Cancer cells derived from the patient's own cells, Destruction by innate and adaptive immune mechanisms requires recognition of non-self features, Mutations that drive cancer development, or occur due to genomic instability, create neo-epitopes that immune cells can recognise

  
• Cancers result from damage to DNA that is mis-repaired, leading to mutations

  
• Different mutagens cause different kinds of DNA damage; different modes of inaccurate repair lead to characteristic mutational signatures
• Researchers analysed coding sequences from 100,000 tumours (and compared with normal tissue in 100 patients)
• Lung and skin cancers (associated with mutagen exposure) had high mutational load: lots of neoepitopes

  
• How did these tumours survive and grow? Why weren't these cancers cells detected and eliminated by the immune system??

  
• CRICOS Provider 00115M
• Key players in immune recognition and killing of "altered self" cancer cells

  antigen-presenting cells (chiefly dendritic cells), CD8+ (cytotoxic) T cells

  
• MED3ATA Cancer Module
• Christine Hawkins
• Antigen-driven activation of tumour-specific CD8+ T cells


  Dendritic cells engulf tumour cells (or pieces of them), Tumour antigens are processed and presented on the dendritic cells' MHC class I molecules, The dendritic cells migrate to lymph nodes, where they can encounter immature CD8+ T cells, If they encounter an immature CD8+ T cell bearing a TCR that recognises the tumour-derived peptide displayed by the dendritic cell's MHC I molecule, this interaction can "activate" the T cell, but only if a second signal is also received via an interaction between CD28 on the T cell and B7 on the dendritic cell, Now activated, the CD8+ T cell is a "cytotoxic" T cell (CTL). It leaves the lymph node and may enter the tumour

  
• Lecture 14.2: Avoiding Immune Destruction Hallmark: Immunotherapy
• Immune evasion through inhibition of activation: CTLA4 upregulation


  If the cytotoxic T cell itself or a regulatory T cell ("Treg") expresses CTLA4, this binds to B7 on the dendritic cell more strongly than CD28, preventing activation of the T cell, Blocking antibodies that bind to CTLA4, preventing it from interacting with B7, can "release the brake" and allow the T cell to be activated, facilitating an anti-tumour immune response

  
• La Trobe University
• Immune evasion through inhibition of activated T cells

  Activated CD8+ T cells encounter tumour cells bearing neo-antigen peptides recognised by their TCR, displayed on MHC I, This triggers the CD8+ T cell to kill the tumour cell, but this signalling is inhibited if PD-1 on the T cell is engaged by PD-L1 on the tumour cell, Blocking antibodies (anti-PD-1 or anti-PD-L1) can disrupt this inhibitory interaction to re-empower the activated tumour-specific CD8+ T cells to kill the tumour cells

  
• Commonwealth of Australia Copyright Act 1968
• Warning: This material has been reproduced and communicated to you by or on behalf of La Trobe University under Section 113P of the Copyright Act 1968 (the Act). The material in this communication may be subject to copyright under the Act. Any further copying or communication of this material by you may be the subject of copyright protection under the Act. Do not remove this notice.
• T cell killing of tumour cells


  In the absence of inhibitory PD-1/PD-L1 signals, ligation of the TCR by MHC bearing a cognate peptide provokes cytoskeletal changes which move cytotoxic granules to the junction between the tumour cell and the T cell, The contents of these granules are released, which induce apoptosis of the target cell

  
• Throughout these cancer lectures: Brown text is examinable, Grey text is just for your interest: not examinable
• Vitale I et al Trends Cell Biol. 2019 May;29(5):396-416
• Immunotherapy options

  • Problem
  • Solution
  • Drawback