Mednotes

L04 Cancer Immunological aspects of cancer

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aliasesL04 Cancer Immunological aspects of cancer

10 min read

Overview

This lecture covers the two-way relationship between cancer and the immune system: how immune suppression and chronic inflammation can cause cancer, how cancer itself suppresses immunity, and how immunotherapy exploits the immune system to fight cancer via immunogenic cell death, cancer vaccines, adoptive T cell transfer, checkpoint inhibitors and CAR T cells. One review-quiz slide’s answer options skip letter (C) in the source material (no content is affected).

Cancer arising from immune suppression and inflammation

  • Cancer (neoplasm/tumour) is uncontrolled cellular growth caused by mutations (e.g. oncogenes) or virus infection (e.g. liver cancer, cervical cancer). Broadly split into leukaemias (including lymphoma) and solid tumours (e.g. melanoma, colorectal cancer).
  • Origins of cancer:
    • Genetic mutations (oncogenes)
    • Viral oncogenes (e.g. HPV) or viral genome integration (e.g. HBV)
    • Immune suppression (e.g. transplant patients)
    • Chronic inflammation (e.g. IBD and colon cancer, HCV, HBV)
  • Transplant patients: immunosuppressants suppress T cells and NK cells, raising the incidence of both viral and spontaneous cancers. Solid cancers more common in transplant patients than the general population include non-Hodgkin lymphoma, lung, liver, kidney and skin cancers (SCC, BCC, melanoma).
  • Chronic inflammation and cancer: increased cellular proliferation raises the risk of mutations and genomic instability; DNA damage can result from reactive oxygen species (ROS) released by neutrophils. Example: hepatitis B and C cause chronic inflammation leading to hepatocellular carcinoma (HCC).
  • Inflammation can also promote cancer by altering the tumour microenvironment: infiltration of tumour-promoting fibroblasts, suppressive macrophages and myeloid-derived suppressor cells (MDSC) helps establish a pro-metastatic niche. The exact mechanisms are complex and not entirely clear.

Immune suppression caused by cancer

  • Neoplastic tissue behaves as a “Darwinian microenvironment” (Balkwill et al.): tumour cells must evade both cell cycle control and the immune system, so surviving cancer is often made up of the “fittest” tumour cells, which divide, evade immunity and produce immunosuppressive factors.
  • This immune suppression can be local (within the tumour) or systemic (often in late-stage disease).
  • Tumour antigens:
    • Tumour-associated antigens (TAA): self-antigens overexpressed by tumours, e.g. PSA, HER2, survivin. Arise from dysregulation of gene expression.
    • Tumour-specific antigens (TSA)/neoantigens: arise from mutations in genomically unstable tumours, e.g. bcr-abl (CML), EGFRvIII, BRCA1/2.
  • Cancer immunoediting: tumours may be eliminated rapidly or persist for months to years, following three phases:
    1. Elimination — tumour destroyed by the immune system.
    2. Equilibrium — immune editing continues, destroying tumour cells with low fitness.
    3. Escape — the tumour has evaded the immune system and grows.
    • Tumour cells in elimination/equilibrium are easier immune targets: they may still express MHC, useful tumour antigens and costimulatory molecules, and retain normal pro-apoptotic pathways. “Escape variants” have lost some or all of these features.

Chemotherapy and immunogenic cell death

  • Chemotherapy (e.g. doxorubicin) induces cancer cell death and can “awaken” the immune system to fight cancer — dying tumour cells can become immunogenic.
  • Dogma held that cell death is a quiet, immunosuppressive process, but radiation and chemotherapy induce severe cellular stress, releasing reactive oxygen species and danger signals (e.g. heat shock proteins).
  • Chemotherapy can also inhibit myeloid-derived suppressor cells (MDSC).
  • Together these effects can make tumour cells immunogenic, breaking the cycle of immune suppression so the immune system destroys tumour cells.

Cancer immunotherapy: vaccines and adoptive T cell therapy

Three main immunotherapy approaches were introduced: cancer vaccines, checkpoint inhibitors and chimeric antigen receptor (CAR) T cells.

  • HPV vaccines (e.g. Gardasil) induce an immune response against viral proteins, preventing infection with oncogenic HPV strains. Vaccinating against tumour antigens directly has not been very successful, but vaccinating against viruses that cause cancer (e.g. HPV) has been.
  • Adoptive T cell therapy pathway (tumour-infiltrating lymphocytes, TIL):
    1. Excise tumour from the patient.
    2. Grow up tumour-infiltrating T cells in vitro from the excised tumour.
    3. Inject activated, tumour-specific T cells back into the patient (intravenously).
    4. Tumour destruction by the activated T cells.
    • Pioneered by Prof Steven Rosenberg. Clinical example: melanoma tumour mass regressed substantially following TIL therapy.

Immune checkpoint inhibitors

  • Anti-cancer T cells can become exhausted or die, so responses are difficult to sustain with conventional T cell therapy alone.
  • Mechanism of tumour immune evasion: the T cell receptor engages antigen/MHC on the cancer cell, but the T cell’s PD1 receptor also binds PD-L1 on the cancer cell surface, delivering an inhibitory signal that suppresses T cell activity (checkpoint pathway).
  • Solution: antibody-based drugs block these inhibitory molecules (e.g. blocking PD-L1) so the T cell can kill the cancer cell.
  • Key checkpoint targets: CTLA-4 and PD-1. Drug examples: ipilimumab (anti-CTLA-4, Yervoy) and pembrolizumab (anti-PD-1, Keytruda).
  • Combination anti-CTLA-4 plus anti-PD-1 therapy gave progression-free survival of around 12 months in stage III/IV melanoma patients.
  • Clinical case: nivolumab therapy produced a partial response in locally advanced unresectable melanoma, with imaging and biopsy showing tumour regression and infiltrating lymphocytes after treatment.
  • Checkpoint inhibitors are slow to act but can keep working even after drug withdrawal, because the immune system continues to attack the tumour once “encouraged.”

CAR T cells

  • Chimeric antigen receptor (CAR) T cells combine an anti-cancer antigen antibody (B cell derived) with T cell signalling components.
  • CAR structure: targeting element (single-chain variable fragment, scFv, derived from a B cell antibody), spacer, transmembrane domain, costimulatory domain (e.g. CD28 or 4-1BB), and the CD3ζ essential signalling domain. The scFv is the “B cell derived” part; spacer, transmembrane, costimulatory and CD3ζ domains are the “T cell derived” signalling parts.
  • Because the CAR binds its cancer antigen directly (not via MHC), CAR T cells are not MHC-restricted. On binding, the T cell releases perforin/granzyme, cytokines (IFNγ/TNFα) and other killing enzymes, killing the cancer cell.
  • Manufacturing/treatment pathway: patient with relapsed/refractory B cell malignancy → leukapheresis to collect blood cells → T cells retrovirally transduced with an anti-CD19 CAR → patient receives preconditioning chemotherapy → anti-CD19 CAR T cells infused back into the patient.
  • Preconditioning chemotherapy depletes suppressive white blood cells and creates space for the CAR T cells to expand.
  • Examples of CAR targets: anti-HER2, anti-CEA, anti-CD19 (for lymphoma/ALL).
  • Case study: Emily Whitehead, diagnosed with ALL at age 6 after failing chemotherapy, was treated with anti-CD19 CAR T cell therapy; she remains cancer-free years later (though she also lacks normal B cells as a consequence).
  • CAR T therapy can cause cytokine release syndrome (CRS), a severe febrile reaction. In Emily Whitehead’s case, an effective treatment chanced upon for her CRS was anti-IL6R (tocilizumab), a drug otherwise used in rheumatoid arthritis.

Self-test

  1. List the four proposed origins of cancer, with one example of each.
  2. Explain why cancer incidence is higher in transplant patients, including the classes of cells suppressed and the categories of cancer that increase.
  3. Describe the mechanism by which chronic inflammation increases cancer risk, giving a named clinical example.
  4. Distinguish tumour-associated antigens (TAA) from tumour-specific antigens/neoantigens (TSA), with an example of each.
  5. Describe the three phases of cancer immunoediting and what distinguishes tumour cells that survive “escape” from those eliminated earlier.
  6. Explain how chemotherapy and radiation can make tumour cell death immunogenic rather than immunosuppressive.
  7. Describe the steps of adoptive T cell (TIL) therapy from tumour excision to tumour destruction.
  8. Describe the checkpoint inhibitory mechanism by which tumours suppress T cells, and how antibody-based checkpoint inhibitor drugs reverse it.
  9. Name a drug that targets CTLA-4 and a drug that targets PD-1, and state the clinical benefit reported for their combination in melanoma.
  10. Describe the structure of a chimeric antigen receptor (CAR), identifying which parts are B cell derived and which are T cell derived.
  11. Explain why CAR T cells are not MHC-restricted, and describe how they kill cancer cells once bound to their target antigen.
  12. Describe the CAR T cell manufacturing and treatment pathway, including the purpose of preconditioning chemotherapy.
  13. What is cytokine release syndrome, and what treatment was used to manage it in Emily Whitehead’s case?
  14. Integrative: explain how both chemotherapy and checkpoint inhibitors can each independently “release the brakes” on the immune response to a tumour, describing the different mechanism each uses.

Answers

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