Cancer Immunology Lecture 1

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Created by
Helena Tang

Cards (26)

  • Key concepts and questions

    1. Tumours need to activate resident innate immunity. How?
    2. Dendritic cells need to activate adaptive immunity in the tumour draining lymph nodes. What do T cells recognise?
    3. Innate and adaptive immune cells need to infiltrate tumours. Do they? Which immune cells do?
    4. The tumour microenvironment interacts with the immune system. How?
  • Key principles

    • The immune system is complex: e.g. dendritic cells, macrophages, neutrophils, mast cells, NK cells, T cells, B cells
    • Each immune cell type can acquire various differentiation states, e.g. inflammatory and tissue repair macrophages, Th1, Th2, Th17, TFH CD4+ T cells, thymic and peripheral Treg, effector and memory-precursor CD8+ T cells, cDC1, cDC2, pDC
    • Immune cell states are dynamic
    • Immune cells interact with each other
    • Any immune response needs to be understood at the systems level
  • Experimental approaches: Immunocompetent mice
    Tumour generation: injection of murine tumour cell lines, genetic manipulation to drive efficient tumourigenesis
    Immunity: endogenous
    Advantages: experimental access – most of existing knowledge has been generated using such model
    Disadvantages: much faster tumour growth, mice are kept sterile
    Potential modification (to investigate T cell function): neo-antigen expression in the tumour cell lines with matching TCR transgenic T cells
  • Key experimental approaches: Immunodeficient mice & System characterisation of human tumour biopsies

    Immunodeficient mice:
    Tumour generation: injection of human tumour cell lines
    Immunity: injection of human immune cells
    Advantages: human cells
    Disadvantages: limited immunity
    System characterisation of human tumour biopsies:
    Tumour generation: endogenous
    Immunity: endogenous
    Advantages: endogenous human anti-tumour immunity
    Disadvantages: limited manipulation
  • Tumour immunity is dynamic
  • Tumours need to active innate immunity

    1. Tumour-induced changes in the tissue need to be recognised
    2. By tissue-resident immune cells, macrophages and dendritic cells
    3. Danger signals and microbes
    4. The outcome of an initial immune response to tissue damage can be repair or chronic inflammation
  • Tumours need to active innate immunity

    1. The cGAS STING pathway as an example
    2. Cytoplasmic double-stranded DNA, e.g. from tumour exosomes, activates cGAS, cyclic GMP-AMP synthase, leading to the generation of cGAMP
    3. cGAMP activates STING, stimulator of interferon genes, by triggering tetramerization on the Golgi, leading to the generation of type I interferons
    4. Thus activated DCs can translocate to the draining lymph nodes
    5. Other danger signals are: RNA (TLR3), ATP (inflammasome), extracellular F-actin (DNGR1 on cDC1 cells)
  • Synthetic STING activation promotes anti-tumour immunity

    1. Chemical compound library screening generates a STING agonist, MSA-2
    2. MSA-2 dimerization is required for STING binding
    3. MDA-2 dimerization is pH-dependent and requires the acidic pH of the tumour microenvironment to be efficient
    4. Oral MSA-2 reduces tumour growth in a mouse model
  • Sustained DC activation promotes antitumour immunity

    1. Migratory cDC1 cells can effectively prime CD8+ T cells in the draining lympho node
    2. cDC1 function becomes diminished over time
    3. Restoration of cDC1 function with anti-CD40 and Flt3 can restore CD8+ T cell priming
  • Macrophages change over time

    1. Tissue-resident macrophages (TRM) activated by danger signals & tumour cell-derived cytokines
    2. Tumours trigger emergency myelopoiesis -> monocytes recruited to tumours developing into: myeloid-derived suppressor cells (MDSC), tumour associated macrophages (TAM)
    3. Low level macrophage activation in metabolically competitive environment -> upregulation of inhibitory receptors, (PD-1, TIM-3), generation of reactive oxygen species (ROS). Switch from the initially immunostimulatory to an immunosuppressive macrophage phenotype
    4. Suppression of T cell function
  • Tumours harbour bacteria
  • T cells can recongnise various antigens
  • Tumours generate neoantigens
  • Tumour immune interactions are diverse
  • Tumour CTL are diverse
  • Tumour T cells are diverse

    CD8+ T cell subtypes (tumour-enriched in black)
    Tn: naïve T cell]
    Tm: (central) memory T cell
    Tem: effector memory T cell
    Trm: tissue-resident memory cell
    Temra: effector memory T cell expressing CD45RA
    Tex: exhausted T cell NK-like
    CD4+ T cell subtypes Tn: naïve T cell]
    Tm: (central) memory T cell
    Treg: regulatory T cell Th1/2/17/fh
  • Exhausted CTL are diverse
    Early/precursor Tex: TCF1+
    Variable inhibitory receptor expression
    Retain some proliferative potential
    Tex with remaining effector function: TOXhi, Granzyme, peforin, IFNg Inhibitory receptor high
    No proliferative potential
    Terminal Tex TOXhi
    Inhibitory receptor high
    No proliferative potential
  • Key principles of the TME (#1)

    • The tumour microenvironement (TME) can be immune–rich (hot tumours) or immunepoor (cold tumours)
    • In immune-rich tumours immune cells can mix with tumour cells or be separated
    • There is a wide variety of immune cells in the TME
    • Anti-tumour immune effectors and suppressive immune cells commonly co-infiltrate
    • There are distinct functional subtypes for most immune cell types
  • Key principles of the TME (#2)

    • Key CTL subtypes are memory, effector memory and exhausted CTL
    • Even exhausted CTL subtype into exhausted cells with residual proliferative potential and terminally exhausted CTL
    • Immune therapy aims for:
    1. Efficient immune infiltration
    2. Efficient mixing of immune cells with tumour cells
    3. Favourable balance of effector to regulatory cells
    4. Generating CTL with proliferative potential over exhaustion
  • Key mechanisms of suppression


    • Tumour microenvironment:
    1. Immune exclusion
    2. Metabolic competition
    3. Suppressive soluble mediators
    • Suppressive cell types:
    1. Treg
    2. MDSC
    • Receptors in T cell activation:
    1. MHCI downregulation
    2. Inhibitory receptors, CTLA-4, PD-1, LAG-3, TIM-3, TIGIT
  • Immune exclusion
  • Immune exclusion can have many possible mechanisms
  • Metabolic competition

    Key metabolic processes for cellular effector function:
    1. Glucose to lactate (Warburg effect), low oxygen, moderate ATP, anabolic precursors
    2. Glucose to TCA, high oxygen, maximal ATP
    3. Glutamine to TCA, anabolic precursors
    4. Amino acid transport, anabolic precursors
  • Metabolic competition

    • The key metabolic competitors:
    Tumour cells
    Macrophages
    T cells
    Key metabolic inhibitors:
    Low glucose
    High Lactate
    Low Glutamine
    Low oxygen
  • Suppressive soluble mediators

    • Prostaglandin E2:
    1. Produced by tumour cells
    2. Generated by COX (cyclo-oxygenase) aspirin, NSAID
    3. Key effect on MDSC
    • Tryptophan depletion:
    1. IDO (indoleamine 2,3-dioxygenase)
    2. Produced by tumour cells and myeloid cells
    • Adenosine
  • Adenosine

    Key concepts:
    • ATP activates the inflammasome
    • CD39 converts ATP to AMP CD73 converts AMP to adenosine
    • CD39 and CD73 are highly expressed by tumour cells, MDSC and Treg
    • Adenosine bind to adenosine receptors A1, A2A, A2B, A3 Adenosine receptor A2A is highly expressed in T cells