Cancer Immunology Lecture 2

• Loss of MHCI


  • MHCI presents cytoplasmic peptides
  • MHCI consists of an HLA heavy chain and b2 microglobulin
  • MHC I is upregulated by type I interferons
  • MHC I is required for antigen presentation to T cells
  • Loss of MHC I sensitises cells to killing by NK cells
  • MHCI expression in cancer

  
• Key features of inhibitory receptors


  • Are commonly expressed as a default part of T cell activation – negative feedback
  • Are commonly upregulated upon induction of T cell exhaustion – persistent antigen expression
  • Are critical for the maintenance of immune homeostasis
  • Are commonly expressed on multiple immune cell types
• Key inhibitory receptors

  
• Key mechanisms of inhibitory receptors


  A: inhibitory signalling, recruitment of tyrosine, serine/threonine and lipid phosphatases to ITIMs and ITSMs (Immunotyrosine inhibitory/switch motifs)

  B: more effective binding to ligands than paired costimulatory receptors

  C: inhibitory signalling, signalling motifs without know homology

  D: Sequestration of costimulatory receptors

  
• CTLA4


  • Upregulated as a default part of T cell activation
  • CTLA-4 is highly expressed on Tregs
  • Ligands are CD80 (B7.1) and CD86 (B7.2), with limited expression mostly on professional APC – key role in T cell priming
  • Ligand competition with CD28
  • Inhibitory signalling in question
  • Ligand depletion: CTLA-4 strips B7 from the APC
  • This only effectively happens on the surface of migratory DCs in a lymph node interacting with regulatory T cells

  
• PD-1


  • Upregulated as a default part of T cell activation
  • PD-1 (as most other inhibitory receptors) is expressed on CD4+ effector, CD4+ regulatory and CD8+ T cells
  • Further upregulation upon T cell exhaustion – persistent antigen \
  • Also expressed on myeloid cells
  • Ligands are PD-L1 and PD-L2 with expression on tumour and immune cells
  • Multiple potential points of action
• TIM-3 – different actions on different cell types


  • The inhibitory receptor TIM-3 limits activation of the cGAS-STING pathway in intra-tumoral dendritic cells by suppressing extracellular DNA uptake
  • TIM-3 restrains anti-tumour immunity by regulating inflammasome activation in migratory DCs
  • TIM-3 allows recognition and phagocytosis of apoptotic bodies via phosphatidylserine
  • TIM-3 is highly expressed on exhausted CTL and inhibits cytolysis of tumour target cells

  
• Antibody drug conjugates

  
• Antibody drug conjugates


  A: Antigen binding

  B: antigen internalisation

  C: lysosomal delivery

  D: lysosomal release

  E: drug action, e.g. DNA damage

  Key mechanisms of resistance:

  Antigen downregulation

  Efflux pump activation

  Drug-specific resistance

  
• Cytokines – IL-2


  • IL-2 drives the proliferation of activated T cells
  • IL-2 binds to the heterotrimeric IL-2 receptor (IL-2Rabg)
  • The IL-2Ra chain is only expressed upon activation of effector T cells
  • The IL-2Ra chain is constitutively expressed on Treg
  • Tregs are highly dependent on IL-2
  • 1992: FDA approval for high dose IL-2 therapy in metastatic renal cell carcinoma
  • Key successes: 20% tumour regression, 9% complete response
  • Key toxicities: leukopenia, nausea, hypotension, fatigue
• Cancer vaccines – key questions

  Choice of antigen:

  Single – multiple

  Conserved – patient-specific neoantigen

  Delivery: Vaccine platform: peptides, mRNA

  Resistance: Tumour-mediated immune suppression
• Checkpoint blockade


  Anti-PD-1: Nivolumab (Opdivo, Bristol-Myers Squibb, 2014), Pembrolizumab (Keytruda, Merck, 2014) plus three later ones

  Anti-PD-L1: Atezolizumab (Tecentriq, Genentech, 2016) plus one later one

  Anti-CTLA-4: Ipilimumab (Yervoy, Bristol-Myers Squibb, 2011) plus one later one

  Considerations of use:

  1. Type of cancer
  2. After previous treatment failure vs. first line treatment
  3. In isolation vs. combination of checkpoint blockers vs. combination with conventional therapy, e.g. radiotherapy and chemotherapy
• Does checkpoint blockade work?

  
• How does checkpoint blockade work?


  • Basal cell carcinoma
  • Isolate tumour biopsies pre and post anti-PD-1 treatment
  • scRNAseq (53,030 cells) plus TCRseq (28,371 T cells)
  • How do T cells change over the course of therapy?

  
• How does checkpoint blockade work?


  Clonal replacement as a key element of the mechanism of anti-PD-1 function

  
• Side effects of checkpoint blockade

  
• Why does checkpoint blockade fail?

  
  

  Tumor Microenvironment:

  • Dominance of immunosuppressive cells (e.g., Tregs, MDSCs).
  • High levels of immunosuppressive cytokines (e.g., TGF-β, IL-10).

  
  

  • Lack of T-cell Infiltration:
  • Presence of "cold" tumors with minimal T-cell presence.

  
  

  • Inadequate T-cell Activation:
  • Poor T-cell priming and activation.
  • Deficiency in necessary costimulatory signals.

  
• Why does checkpoint blockade fail?


  • Impaired Antigen Presentation:
  • Low mutational burden or neoantigen levels.
  • Loss or downregulation of MHC class I.
  • Cancer Cell Resistance:
  • Genetic mutations promoting survival.
  • Evolution of adaptive resistance mechanisms.
  • Patient-Specific Factors:
  • Genetic variability affecting immune response.
  • Impact of previous treatments on immune system.
  • Checkpoint Inhibitor Specificity:
  • Reliance on single-agent targeting one pathway.