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CAN > Tumour immunology > Flashcards

Tumour immunology Flashcards

1
Q

What did Coley prove when he injected patients with bacterial extracts?

A

It activated the general systemic immune system to reduce tumours in some Pts.

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2
Q

What does immunogenic mean?

A

Can induce an immune response in host

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3
Q

How was it proven that tumours are immunogenic?

A

Live tumour cells give to a naive mouse would develop cancer.
Vaccination of a naive mouse with irradicated tumours cells prevents tumour development when exposed to the live tumour cells.

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4
Q

How was it proven that tumours can induce immunological memory?

A

Mice were protected by previous exposure.
A mouse that had already had the tumour successfully removed would not develop the tumour again when exposed to live cells.
A naive mouse exposed to live tumour cells developed the tumour.

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5
Q

What evidence suggests that T cells play a role in the immune defence?

A

Tumour protection is not seen in mice who are T cell deficient but it can be induced by adoptive transfer of T cells from immune mice.

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6
Q

What human evidence is there about the immune system?

A

Immunosuppressed Pts more frequently develop cancer, particularly viral related.
Cancer Pts can develop their own spontaneous response to tumour.
Presence of immune cells within a tumour can correlate to improved prognosis

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7
Q

What is cancer immunosurveillance?

A

It predicts that the immune system can recognise precursors of cancer and destroy them before they become clinically apparent.

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8
Q

What is cancer immunoediting?

A

The ability of the immune system to change the immunogenicity of a tumour that may eventually form. It involves the 3 E’s.

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9
Q

What are the 3 E’s of immunoediting?

A

Elimination - Immune mediated destruction of most cancer cells quickly on recognition.
Equilibrium - Dynamic equilibrium between the immune system and a tumour cell that survived elimination. The response can contain the cell but not fully remove it.
Escape - Tumour cell variants grow out in an immunologically intact environment, away from the equilibrium to become a clinically apparent cancer.

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10
Q

How do T cells detect antigens?

A

TCR recognises antigens on APCs in the form of short peptide fragments bound to MHC molecules. CD8 and CD4 are bound to a cytoplasmic TK through its tail to allow it to interact with TCR for increasing sensitivity to antigens.

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11
Q

What does a TCR require to fully activate a resting T cell?

A

TCR signal is not sufficient on own but requires costimulatory 2nd signal through CD4/8 binding to MHC and CD28 binding to CD80/86 of the APC.

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12
Q

How is a T cell involved in destroying cancer?

A

When a tissue is damaged by cancer treatment, tumour antigens are released. These are processed by DC and present to specific T cell that recognises the antigen within the lymphatic system. If recognised the T cell clonally expands and enters the circulation to attack the tumour.

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13
Q

What are the 6 types of tumour antigens?

A
  • Mutated self proteins
  • Aberrantly or overexpressed self proteins
  • Lineage specific
  • Abnormal post translational modification of self protein
  • Viral proteins
  • Tumour stroma
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14
Q

What are mutated self proteins? What causes it?

A

A mutation of a protein the is present in normal cells causing the cell to present as foreign and is targeted by the immune system. May be caused by DNA damage

e. g. cdks in melanoma
e. g. beta catenin in melanoma
e. g. caspase 8 in squamous cell carcinoma

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15
Q

What is an aberrantly or overexpressed self protein?

A

A protein that is present in higher levels than normal or is present at the wrong time
e.g. oncofetal antigen and telomerase

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16
Q

What is a lineage specific protein?

A

Expressed on tumour cells and matches one type of a normal cell
e.g. Ig on B cells in lymphomas

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17
Q

What is an abnormal post-translational modified self protein?

A

Alteration in the normal modifications of a protein

e.g. mucin is overexpressed in underglycosylated form in breast cancer

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18
Q

What is a viral protein?

A

A cell can carry and express viral proteins making them a foreign target
e.g. HPV in cervial and EBV in Hodgkin’s

19
Q

What is the significance of the tumour stroma as an antigen?

A

Tumour endothelial markers may be abnormal in structure, appearance and genoma

20
Q

What would be the ideal target antigen for therapy?

A

An antigen that is tumour specific to reduce toxicity on normal cells.
Shared amongst all Pts with the same tumour type so it is widely applicable.
Target the antigen that is critical for tumour growth and survival.
Lack of immunological tolerance - Must bind with high affinity to T cell to prevent tolerance and anergy.

21
Q

Why is it important to target an antigen that is critical for growth and survival?

A

Targeting an antigen that is not crucial, will create an immune pressure that will cause the antigen to mutate and so it can no longer be targeted = antigen loss

22
Q

How can a tumour escape the immune system? (7)

A
  • Loss of HLA class 1 expression = can’t present tumour antigen to T cell
  • Reduced expression of molecules involved in antigen processing e.g. downregulated TAP needed to export MHC onto membrane.
  • Loss of costimulatory molecules
  • Loss of adhesion molecules in APC and lymphocytes
  • Loss of target antigen
  • Inhibition of T cell infiltration
  • Immunosupression at the tumour site
23
Q

How is T cell infiltration inhibited?

A

Endothelin B receptor expression on tumour endothelium prevents modulation of ICAM to reduce the adhesion of T cells to the endothelium so that it cannot leave the bloodstream.
Nitrosylation of chemokines prevents a signal being produced that would attract T cells to the site.

24
Q

How does immunosuppression occur at the tumour site? (6 ways)

A

1) Transforming GFbeta suppresses anti-tumour T cell function and induces Treg.
TGFbeta is a natural suppressor of immune response that is overexpressed in tumours.
2) IDO catabolises tryptophan (AA) to block CD8 proliferation and promote apoptosis of CD4 cells as the depletion of the essential AA in the environment means the T cells cannot function fully.
3) Factors inhibit DC maturation and function so that the DC mediates immunosupressive effects and promotes T reg differentiation e.g. IL-6, VEGF
4) CD95L expressing tumour induces death of a T cell expressing CD95 by fas ligand.
5) Regulatory T cells inhibit immune response. Can be selectively recruited to stroma by chemokines to suppress anti-tumour T cells when they arrive
6) Myeloid deprived suppressor cells - A population of cells that comprise myeloid progenitors that expand and differentiate in cancer and infection to suppress T cell function.

25
Q

What is non-specific T cell stimulation therapy?

A

Uses immnostimulatory cytokines. Inject T cell GF into body to increase the T cell levels for an enhanced response. e.g. IL-2 for melanoma and RCC.

26
Q

What is the problem with using IL-2 as a stimulating cytokine in therapy?

A

It is toxic at high levels causing leaky capillary syndrome.

27
Q

How are T cells regulated in a normal immune response using CTLA4?

A

CTLA4 is a checkpoint inhibitor which binds CD80/86 on APC more strongly than CD28 on in order to suppress T cells as it prevents the costimulatory signal. Used to prevent an overexaggerated immune response. CTLA4 is upregulated on T cell surfaces as they become active.

28
Q

What therapy is target at CTLA4 in non-specific T cell stimulation therapy?

A

Cancer cells have adopted CTLA4 suppression so a therapy is to block this interaction using antagonistic Igs that bind to the inhibitor receptor CTLA4 on T cells to keep them active.

29
Q

How can a vaccination be used as a therapy?

A

Using tumour cells that are irradicated can induce an immune response in the Pt without developing cancer. The cells are combined with costimulatory CD80/86 molecules or cytokines to enhance the immunogenicity of the tumour cell.
Can use peptides or protein antigens expressed from recombinant viruses.
Can used DC based vaccines

30
Q

What therapies are used under adoptive T cell therapy?

A
  • T cell infusion
  • Tumour specific T cell infusion
  • TIL therapy
  • CARs
31
Q

What is the risk of T cell infusion?

A

Infusing whole T cell populations from donor lymphocytes may cause graft v host disease, where the donor T cells views the host as foreign. Used in CML patients

32
Q

What happens in tumour specific T cell infusion?

A

T cells specific to a tumour antigen are selected and enhanced to achieve a high frequency of reaction and then expanded into a population before being but back into the Pt.

33
Q

What is TIL therapy?

A

By using a biopsy, tumour infiltating lymphocytes that are specific are selected and expanded into a popualtion. Pt is given high dose of IL-2 along with the lymphocytes.

34
Q

What does a Pt who is going to undergo TIL therapy require?

A

Non-myeloablative conditioning - Deplete the immune system to create space and all a better response to the GF IL-2.

35
Q

What is CARs therapy?

A

Chimeric antigen receptors and engineered T cells. Create monoclonal antibodies to recognise the tumour antigen. The antibody is transferred into a T cell via a retrovirus so that the T cell produces the modified receptor. The tumour specific T cells are injected into the Pt.

36
Q

Why is CARs therapy beneficial?

A

No issue with the rare T cell specific receptors as creating their own.

37
Q

What are the potential side effects of TIL and non specific CTLA4 stimulation?

A

AI - especially with TIL therapy which results in melanoctye destruction resulting in vitiligo and uvetitis. Risk of blind or deafness if targets normal cells.
Antagonistic Igs in CTLA4 therapy resulted in severe AI responses as all T cells are activated so risk of activating a TCR that detects host tissue.

38
Q

What do monoclonal Igs cause?

A

An immune mediated mechanism of either

  • Complement mediated lysis e.g. Rituximab binds to CD20 of tumour
  • ADCC e.g. Rituximab binds to CD20 to activate NK cells which interact with FCyRIII
39
Q

What direct effects can monoclonal Igs cause?

A

Block receptor-ligand interactions to block proliferation and induce apoptosis in cancer cells.
Antiangiogensis

40
Q

Give an example of a monoclonal Ig that has a direct effect.

A

Herceptin inhibits the binding of ligands to GF recptor HER1 and HER2 to block proliferation of HER expressing cells through inhibition of MAPK signalling.

41
Q

How is antiangiogensis induced and waht drug is used?

A

Avastin blocks VEGF receptor interaction.

42
Q

Which therapy is Avastin used along side and why?

A

Used in combination with cytotoxic drugs as avastin normalises vasculature for a more efficient delivery of chemo in vessels.

43
Q

What compounds can be conjugated to an Ig to give it cytotoxic activity?

A

Ig bound to radionuclei to induce DNA damage and apoptosis e.g. iodine
Ig bound to a protein toxin molecule
Ig bound to cytotoxic drug

CAN (16 decks)

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