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Cancer, Autoimmunity and Transplant Immunology > Cancer and the Immune System > Flashcards

Cancer and the Immune System Flashcards

1
Q

what genetic disorder can abrogate the immune system?

A

Severe Combined Immunodeficiency (SCID)
- Genetic disorder that dramatically weakens the immune system
- patients unable to generate T and B cells
- Patients usually die within 1 year due to severe, recurrent infections

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2
Q

how is SCID treated?

A

Treatment is haematopoietic stem cell transplant from donor to reconstitute immune system

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3
Q

why is the immune system important in cancer?

A

Cells can continuously go wrong – DNA damage
- Immune system can recognise and clear these cells of ‘altered self’ without any sign of symptoms

Immunosurveillance against cancer is critical
- Immune cells continually survey the body for damaged or altered cells, which appear different to the immune system and can be cleared

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4
Q

what are the anti-immune hallmarks of cancer?

A

Avoiding immune destruction – prevent destruction by immunosurveillance

Tumour-promoting inflammation – generate TME for cancer growth

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5
Q

what makes tumour development more likely?

A

the impairment or repression of innate and/or adaptive immunity

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6
Q

what early evidence limited our understanding of cancer immunosurveillance?

A

Immunodeficient athymic nude mice were given Methylcholanthrene(MCA), a highly carcinogenic polycyclic hydrocarbon which readily induces primary sarcomas in mice
- However, no increased incidence of spontaneous or chemically induced tumours was seen - these negative results damaged the field of cancer immunology

But: Subsequently realised that athymic mice have NK cells and low frequencies of T cells, sufficient for immune surveillance

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7
Q

what mouse model was useful in studying cancer immunity?

A

Genetically modified K/O mice with depletion of one or more arms of immune system e.g. B cells, T cells, NK cells - removal of the immune system
- Treated with MCA carcinogen
-

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8
Q

how were NK cells shown to be important in cancer immunosurveillance?

A

NK/NKT cell depletion:
- C57BL/6 mice are 2-3x more susceptible to tumours induced by MCA
- NK cells important for preventing cancer

when NK cells were activated with a-galactosylceramide, C57BL/6 mice had reduced tumour incidence

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9
Q

how were cytotoxic functions of immune cells shown to be important in cancer immunity?

A

K/O function of immune cells
- T cells and NK cells can kill by perforin/granzyme or by Fas (Fas L on T cell binds Fas on cell = apoptosis)

If perforin is K/O – mice have increased susceptibility to MCA-induced cancer – B cell lymphoma
- lesser role of Fas

Function of T and NK cells crucial for cancer surveillance

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10
Q

what is RAG2?

A

RAG2 important for recombination of T cells and B cells

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11
Q

what happens when RAG2 is K/O? how does this effect cancer incidence?

A

Loss of Rag2 function leads to the total inability to initiate VDJ rearrangement
- Rag2-/- mice have no mature T or B lymphocytes
- These mice were susceptible to developing tumours

Functional T, NK and B cells are essential to suppress tumour development
- Supporting the idea that the immune system can recognise and eliminate cancer

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12
Q

what are examples of primary immunodeficiencies or inborn errors of immunity?

A

SCID – most severe – defects in common gamma chain of cytokine receptors involved in T cell and B cell development

CVID - CVID (common variable immunodeficiency) defective humoral immunity due to defective T cell-B cell interactions

X-linked agammaglobulinaemia – cant form mature B cells or antibodies

MHCII deficiency – cant make mature CD4 T cells

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13
Q

how do immunodeficiencies affect cancer incidence?

A

Primary immunodeficiencies or inborn errors of immunity (IEI) affect approximately 1:10,000 births
- increased cancer risk estimated to be 4-25%, depending on the genetic difference and immune cells affected

SCID
NHL (non-Hodgkin lymphoma), Hodgkin Lymphoma, renal carcinoma, various leukaemias

CVID
NHL and epithelial tumours of stomach, breast and bladder

Evidence in humans where immune system is diminished that causes cancer

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14
Q

what are secondary immunodeficiencies?

A

e.g. due to immunosuppressive medication
- standard treatment after solid organ transplant to prevent graft rejection
- Often life-long treatment

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15
Q

how can immunosuppressive medication be linked to cancer?

A

Immunosuppressive medication can enable reactivation of oncogenic viruses that are normally contained by the immune system
- e.g. EBV infects B and epithelial cells – cancers are in B cell lymphomas and epithelial carcinomas
- Normally EBV is contained by T cell mediated immunity
- In a patient on immunosuppressive drug, there is loss of T cells, so no control of EBV = cancer

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16
Q

what is an example of a patient who had viral reactivation due to secondary immunosuppression?

A

Patient who had transplant and was immunosuppressed:
- Monitored for EBV reactivation
- After 60 days, EBV load increases – reactivation of oncolytic virus
- PET scan – areas of high activity – see lymphoma formed as T cells were suppressed

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17
Q

can secondary immunodeficiency also cause non-viral induced cancer?

A

Viruses and non-viruses can induce cancer
- Immune system surveilling against cancer – if it is suppressed, this can increase risk of non-virus-associated cancer

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18
Q

what is Coley’s toxin?

A

Early clinicians observed that in rare cases, infection can lead to spontaneous cancer regression:
- Coley attempted to treat soft-tissue sarcoma by injecting a mixture of bacteria into the tumours to induce an immune response
- He reported a 10% cure rate
- the immune response to the bacteria at the tumour site also induced a response against the cancer

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19
Q

what is the first line treatment for bladder cancer?

A

Injection of the BCG vaccine into the bladder is still used as a first-line treatment for bladder cancer
- Not entirely clear how this works
- Appears to stimulate immune activation in the lining of the bladder which can lead to an anti-cancer response

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20
Q

what immune cells can infiltrate tumours?

A

Immunohistochemistry of TME:
- CD3 T cells
- CD8 T cells
- CD16 NK cells
- FOXP3 Tregs
- CD20 B cells
- CD68 macrophages

Many different immune cells inside TME – promotion of inflammation

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21
Q

how do tumour-infiltrating lymphocytes (TILs)
predict clinical outcome?

A

Immune infiltration can influence patient prognosis:
- high TILs in tumour = longer survival
- low TILs in tumour = shorter survival

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22
Q

how can different types of immune cell infiltration be important in cancer?

A

Percentage of CD4+ T cells in tumour infiltrates is prognostic in DLBCL:
- biggest increase in survival if CD4 T cells infiltrated the tumour compared to CD8 infiltration

The quality and/or quantity of immune infiltrating cells appear to represent independent prognostic factors – determine outcome of patients

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23
Q

how do different TMEs affect immune cell function and inflammation?

A

the overall contribution of the local inflammatory and immune system are profoundly influenced by the type of tumour
- Many different immune cells in TME
- If immune cells cant function in the TME due to immune checkpoints expressed by cancer, there are poorer outcomes
- T cells being there isn’t enough, they need to be able to function

24
Q

what are abscopal effects?

A

systemic anti-tumour immunity
- treatment of one tumour can indirectly induce anti-tumour immunity in distal lesions

25
Q

how does ionising radiation alter the TME?

A

Induces immunogenic cell death involving:
- Translocation of calreticulin to cell surface
- Allows DC uptake via scavenger receptors
- Release of HMGB-1 - Binds TLR4 and promotes cross presentation
- Release of ATP - Binds to P2X7 and activates inflammasome

exposes cancer antigens and DAMPs to stimulate the immune system - taken up by dendritic cells

26
Q

how does radiotherapy stimulate the immune system?

A

Immune cells inside tumour may be in passive state before radiotherapy:
- Radiotherapy bursts open tumour cells
- release of DAMPs
- DAMPs sensed by DCs via TLRs
- DCs take up cancer antigens
- DCs enter draining lymph node and stimulate T cell response

27
Q

what evidence is there of radiotherapy causing abscopal effects?

A

Immune responses generated by local ionising irradiation can lead to regression of metastatic tumours at distant sites
- Patient with metastatic melanoma given ionising radiation on metastic spinal tumour mass
- Led to regression of other metastases in the lymph nodes and spleen over 4 months
- this effect was maintained over many years and induced long-term survival

28
Q

why is anti-cancer T cell immunity difficult to induce?

A

Complex TME – DCs and lymphocytes may be suppressed
- DCs need to be able to leave to stimulate T cells, and T cells need to be able to come back - difficult

29
Q

why is it difficult for the immune system to detect cancer?

A

Cancer arises from normal cells so are extremely similar
– harder to distinguish cancer from self compared to pathogens

30
Q

why is it difficult for T cells to recognise cancer?

A

Tolerance:
- Diverstiy in TCRs – VDJ recombination = 10^18 possibilities of TCR sequence
- Many T cells are removed as they are self-reactive so bind too strongly, or not functional as they bind too weakly
- T cells that recognise self are largely deleted during dev to avoid autoimmunity
- All the T cells that would have recognised cancer are deleted due to tolerance

31
Q

what cancer features can T cells recognise?

A

T cells can recognise proteins that appear as ‘foreign’ to the immune system

32
Q

what are examples of cancer antigens that appear foreign?

A

Viral antigens in viral-associated cancer
- Tumour expressing viral proteins e.g. EBV antigens which are presented on surface and recognised by T cells

Tumour-specific antigens e.g. WT1 in AML
WT1 not normally expressed in adulthood but is re-expressed in cancer due to demethylation and surface presentation

Tissue-specific antigen expression

Overexpression of proteins
- T cells can recognise when a protein is overexpressed e.g. HER2

33
Q

how are neoantigens generated by cancer?

A

Cancer is a consequence of mutation:
- DNA mutation may lead to expression of a protein that has a change in genetic code – change in amino acid sequence – change in protein
- If this part of protein can be presented, T cell will recognise it as it is altered-self
- T cell doesn’t recognise normal cell, but can recognise cancer cell with the mutated peptide

34
Q

why are neoantigens important in cancer immunosurveillance?

A

Normal cell = self proteins which immune system is tolerant to

Cancer = neoantigens where protein has been changed by DNA mutation – neoepitope is presented on the surface to T cell
- Neoepitopes look foreign to the immune system

35
Q

what does a good immune response to cancer depend on?

A

Mutational load = number of DNA mutations in a cancer type

36
Q

how do mutational loads vary among cancers?

A

Some cancers have many more mutations compared to others
- Cancers with most mutations are melanoma – caused by exposure to UV which can constantly happen
- Lung cancer is also high in mutational load – smoking
- Leukaemias have less mutational load

37
Q

what cancers are more amenable to immunotherapies?

A

Cancers amenable to immunotherapy tend to be ones with high mutational load as higher chance of neoantigens which can be recognised by immune system

38
Q

what are the key immune evasion mechanisms in cancer?

A
  1. release of immunosuppressive cytokines
  2. downregulation of MHC or antigen processing pathways
  3. exploiting T cell checkpoints
39
Q

what immunosuppressive cytokines can be released in the TME?

A

Immune cells in TME can be suppressed:
- Tumour makes cytokines such as TGFb or IL-10 that are released to suppress T cells
- Cytokines may be made by tumour cells or other suppressive cells in TME such as Tregs and MDSCs

40
Q

what is the key feature of TMEs?

A

TME is complex and is very immunosuppressive to T cells
- T cells tend to be unable to function in TME

41
Q

how do cancers impair T cell recognition?

A

Tumours downregulate MHC:
- T cell response requires MHC for presentation of processed antigen
- Cancers prevent T cell recognition as they downregulate MHC

Adenocarcinoma – stained for MHC
- Tumours have no brown MHC staining, surrounded by MHC-positive stromal cells

42
Q

as well as downregulating MHC, how else can cancers reduce antigen presentation?

A

Downregulation of components of processing pathway:
- Protein processed by proteosome and translocated by TAP into ER to be loaded onto MHC

In Burkitt lymphoma – mutation in TAP – peptides cant be translocated into ER so aren’t loaded onto MHC

43
Q

what are immune checkpoints?

A

T cells have checkpoints: ‘Emergency OFF-switches’
- Important in regulating immune responses
- PD-1 is important for immunity
- In viral infection when T cells expand, they need to be resolved eventually – PD-1 prevents overactive immune system to stop excessive tissue damage

44
Q

how do cancers exploit immune checkpoints?

A

Cancer expresses the ligand that binds to T cell checkpoints such as PD- L1
- PD-L1 on cancer binds PD-1 checkpoint on T cell to inhibit the T cell

45
Q

how can the immune system cause tumours to evolve?

A

Selection pressure by immune system can cause outgrowth of cancers
- Cancers can survive immune system
- If 2 or 3 cells downregulate MHC, these can escape CD8s and NK cells, and these fittest cancers survive
- causes an outgrowth of cells that can evade immune system

46
Q

why can cancer recurrence occur to chemo/radiotherapy?

A

Cancer cells are subject to evolutionary pressure, and only the ‘fittest’ cells survive
- Explains why recurrent cancer is harder to treat – the surviving cancers evolve to become resistant to the therapy so will persist despite treatment

47
Q

what type of antigens might T cells recognise in cancer?

A
  1. tumour-associated antigens
  2. tumour-specific antigens/neoantigens (mutated self-antigens)
    - e.g. BCR-ABL fusion protein
  3. viral antigens e.g. EBV
  4. aberrantly expressed self-proteins e.g. WT1 (TF that drives proliferation during development) or HER2
    - Low avidity T cell can bind cell coated with abnormally high expression of an antigen
  5. differentiation/cell lineage antigens
    - e.g. CD19 tissue-specific antigen, targeted by CAR-T therapy
  6. abnormal post-translational modification of self-protein
    - e.g. MUC-1 - epitope looks different
48
Q

what are the characteristics of a good T cell antigen?

A
  • Needs to be altered enough from self to avoid autoimmunity
  • lack of immunological tolerance so that high avidity T cells recognise altered-self
  • Needs to be expressed only in cancers – tumour-specific to avoid toxicity
  • Antigen that is present in all the tumours
  • Avoid selection pressure that enables small proportion of cancers to survive – prevents regression and eliminates entire tumour
  • The antigen needs to be critical for growth and survival of the tumour cell
  • Antigens that are shared amongst people with different tumour types – widely applicable
49
Q

how may tumours escape T cell surveillance?

A
  1. downregulation of MHC
  2. suppress/change expression of different antigens
  3. immunosuppression
  4. metabolic depletion
  5. impaired migration
  6. immune tolerance/lack of suitable target antigens
50
Q

how may cancers downregulate MHC?

A

Tumours can downregulate MHCI to reduce antigen presentation - E.g. Burkitt’s lymphoma downregulates TAP, so reduced MHCI loading in the ER

C2TA controls MHCII cassette expression – cancers can also downregulate this

51
Q

how do cancers suppress/change their antigens?

A

Suppress expression or change expression of different antigens – epigenetic modifications
Antigen loss variants – downregulation of antigen due to selection pressures from immune system allowing tumours to evolve
- T cell targeting results in selection of malignant cells that do not express the target antigen

52
Q

how may T cells be suppressed in the TME?

A
  • Tumour secretes or expresses factors/immune checkpoint ligands to inhibit T cells e.g. PD-1
  • Tregs in TME use up IL-2
  • Tumour, Tregs, MDSCs and M2 macrophages release IL-10, TGFb
53
Q

how may T cell metabolism be impaired in the TME?

A

dampens T cell metabolism by cancer excessive consumption of nutrients
- Tumours take up trypsin and arginine which are essential for T cells – depleted from environment

54
Q

how are T cells excluded from the TME?

A

Stroma can present proteins which impair T cell migration into tumour – exclusion from TME
- chemokine inhibition

55
Q

how may cancers be immune tolerant?

A

No immunogenic antigen or T cells specific for suitable “self” antigens have been deleted

Cancer, Autoimmunity and Transplant Immunology (15 decks)

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