L6: Cancer Immunology

Question 1

What are the functions of innate immune system?

Answer 1

• first line of defence
• not educated
• not specific
• ready to respond to common infections

Question 2

What are the functions of adaptive immune system?

Answer 2

• more versatile
• memory
• educated
• highly specific
• slower, takes time to develop

Question 3

What is Burnet and Thomas theory of cancer immunosurveilance?

Answer 3

• Lymphocytes act to patrol tissues looking for and destroying continuously arising transformed cells
• Therefore, if cancer is to arise it must overcome the ability of the immune system to hold it at bay

Question 4

How is a T cell activated?

Answer 4

• Through antigen presenting cells / dendritic cells
• MHC II makes a complex with TCR - signal 1
• CD80/86 makes a complex with CD28 - signal 2
• these promote T cell survival and proliferation
• cytokines excreted - signal 3
• promotes nature of a T cell

Question 5

How do tumours evade T cell response?

Answer 5

• tumour antigens are ‘self-antigens’, which we tolerate
• cancer downregulates MHC class molecules - poor antigen presentation
• hijack normal physiological mechanisms for T-cell regulation

Question 6

How do cancer cells orchestrate the microenviroment in which they reside?

Answer 6

• Use chemokines and cytokines to recruit and re-educate immune cells to promote tumour growth
  These are:
• Low molecular weight proteins secreted from cells into the surrounding environment
• can recruit, activate, re-educate and expand immune cell populations to support tumour cell survival and progression
• environment orchestrated by bi-directional paracrine signalling networks based on chemokine ligand-receptor interaction

Question 7

What are the cell types that reside within TME that can help evade T-cell response?

Answer 7

• Regulatory T cell – a type of CD40 cell, can engage with CD80 cells in order to suppress CD80 function. Upregulates granzyme, performin, IL10 and IDO (makes TME metabolically hostile to the CD80 cells
• M2 Macrophages – similar mechanisms, express Arg1 (metabolism involved), express PD-L1&2
• MDSC

Question 8

What are the two mechanisms for PD-L1 upregulation by tumour cells?

Answer 8

1. Innate Resistance (Constitutive Mechanism)
   * Mechanism:
   o Tumor cells inherently upregulate PD-L1 due to oncogenic signaling pathways (e.g., mutations or activation of pathways like PI3K/AKT, RAS/RAF/MEK).
   o This constitutive expression is independent of immune system activity.
   o PD-L1 is expressed on tumor cells, directly binding to PD-1 on T-cells.
   o This interaction inhibits T-cell activation and cytotoxicity, promoting immune evasion.
   * Key Features:
   o Driven by intrinsic tumor signaling without immune system involvement.
   o Resistant to immune surveillance from the outset (hence “innate resistance”).
2. Adaptive Resistance (Immune-Driven Mechanism)
   * Mechanism:
   o PD-L1 expression is induced as a response to immune system activity.
   o Activated T-cells recognize tumor antigens and release interferon-gamma (IFN-γ).
   o IFN-γ triggers the STAT pathway in tumor cells, leading to the transcriptional upregulation of PD-L1.
   o The increased PD-L1 on tumor cells binds to PD-1 on T-cells, inhibiting their function and creating a feedback loop that suppresses the immune response.
   * Key Features:
   o Reflects an immune reaction by the tumor microenvironment (adaptive immune resistance).
   o PD-L1 upregulation occurs in response to the presence of T-cells and cytokines like IFN-γ.