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Year 2 - MCD Immunology > Tumour Immunology > Flashcards

Tumour Immunology Flashcards

1
Q

Example for immune surveillance

A

Patient developed vertigo, unintelligible speech & ataxia
• diagnosed w. breast cancer

BUT

tumour produced CDR2
• bodies made Abs against these
• BUT these antigens also found in cerebellar purkinje cell neurones SO = brain degeneration also occured

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2
Q

What 3 things does the ‘breast cancer case’ teach us

A
  1. Some tumours can express antigens normally absent from (or not detectable in) corresponding normal tissues
  2. The IS can detect & launch an attack on the abnormally expressed antigens/tumours
  3. In certain cases, this may result in A.I destruction of normal somatic tissues
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3
Q

Circumstantial evidence for immune control of tumours?

A

o Many microscopic colonies of cancer cells have been found in people that are controlled well and do not develop and so possibly explain control/immunity from some cancers

o Patients treated for melanoma and are free from disease that become organ donors can also induce melanoma in the donor recipients – so the donor had some immunity to melanoma

  • Suggests that the I.S has capability to keep cancer under control *
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4
Q

Explain the Cancer-Immunity cycle

A
  1. Cancer cells release cancer-specific antigens
  2. APCs take up the cancer antigens
  3. APCs prime the T-cells in the lymph nodes to the antigens
  4. T-cells migrate to tumour (CTLs)
  5. T-cells infiltrate tumour
    • TIL = Tumour Infiltrating Lymphocytes
  6. T-cells recognise tumour
  7. T-cells kill tumour
    • cycle then repeats as cellular contents released
    • this will result in immune selection pressure which can result in loss of tumour MHC expression – like how bacteria avoid antibiotics
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5
Q

Explain the cancer pathogenesis - the tumour growth

A 
Tumour growth (eventually) results in inflammatory signals
 • this recruits the innate immune response and subsequent recruitment of adaptive, antigen-specific immunity

Small tumours
• do NOT cause a lot of inflammation and is a problem (whereas viruses instantly start the immune response as LOTS of inflammation)
• if there is no co-stimulation coming from inflammation, there may be anergy of the immune cells

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6
Q

Summary of requirements for activation of an adaptive anti-tumour I.R?

A
  1. Local inflammation in tumour

2. Expression and recognition of tumour antigens

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7
Q

What are the potential problems in Immune Surveillance of cancer?

A
  1. It takes a while for the tumour to cause LOCAL INFLAMMATION
  2. Antigenic differences between the NORMAL vs. TUMOUR cells can be very subtle
    • HENCE hard to pick up on by the APCs
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8
Q

What can we therefore do if the above condition for Immune Surveillance of cancer is NOT met?

A

CANCER IMMUNOTHERAPY!

If the above conditions are NOT met or fail to spontaneously active the adaptive immune response, we can “teach” the adaptive immune response to selectively detect and destroy tumour cells

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9
Q

How is the I.R to viruses similar to that of tumours?

A

T-cells can detect the health of the inside of the cell
• via. MHC molecule functions
• most tumour antigens are CYTOSOLIC antigens

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10
Q

What can tumour-specific antigens be separated into?

A
  1. Viral proteins
    • that cause cancers
  2. Mutated cellular proteins
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11
Q

Explain the cancers of viral origins

A

(1) Opportunistic malignancies - immunosuppression

  • EBV-positive lymphoma (post-transplant immunosuppression)
  • HHV8-positive Kaposi sarcoma (HIV individuals)

(2) Immunocompetent individuals

  • HTVLI-associated leukaemia
  • HepB/C associated hepatocellular carcinoma
  • HPV+ genital tumours
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12
Q

Explain HPV and cervical cancer

A

Cervical cancer is induced and maintained by E6 and E7 intracellular onco-proteins of HPV.
• we do NOT target these antigens (E6, E7) for a preventative HPV vaccine SO use structural proteins instead to make virus-like proteins

 >99% of the population is develops immunity to HPV-16 infection but <1% do not and may develop cervical neoplasia
– here, preventative or therapeutic vaccination could be useful.

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13
Q

Name of vaccination against HPV?

A

Gardasil 9

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14
Q

Explain TAA

A

Tumour-associated antigens

these are NORMAL cellular proteins which are aberrantly expressed
• NOT mutated
• because they are normal self-proteins, tolerance may need to be overcome for an I.R to occur

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15
Q

Examples of TAAs?

A

Cancer-testese antigens
• NOT expressed in normal adult tissues except male germ cells
• SOME expressed in placenta

MAGE (melanoma associated antigens)
• identifies in melanoma & expressed in other tumours

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16
Q

Specific examples of TAAs?

A

o HER2 – Human Epidermal Growth Factor Receptor 2
– overexpressed in some breast cancers

o MUC-1 (Mucin-1)
– membrane-associated glycoprotein overexpressed in many cancers

o CEA (Carcinoembryonic antigen) 
 – normally only expressed in foetal/embryo, but overexpressed in cancers

o Prostate antigens
– PSA (prostate-specific antigen), PSMA (prostate-specific membrane antigen), PAP (prostatic acid phosphatase)

17
Q

Example of molecule that be considered BOTH Tumour Associated & Tumour Specific Antigen?

A

p53

  • TAA - when it is OVEREXPRESSED
  • TSA - when it becomes MUTATED
18
Q

Why is Tolerance an issue in cancer immunotherapy

A

Tolerance induction is via. -VE selection in the thymus
• CENTRAL TOLERANCE
• T-cells that react w. self-antigens are deleted during selection in the thymus

19
Q

How can tolerance be used in immunotherapy?

A

This central tolerance is NOT perfect and we all have some potential auto-reactive T-cells in our repertoire
• some of these cells have some use in immunotherapy in tumour treatment against TAAs if we can inhibit the tolerance OR stimulate their expression

20
Q

Explain the issue with Immunotherapy in regards to TAA and AI

A

If you generate an I.R agaisnt TAA

• could cause an A.I type problem as the TAA are NORMAL proteins that can be found elsewhere around the body

21
Q

Explain an example of TAA and A.I problems

A

Tyrosinase is a differentiation-type antigen
• lots of people have poor tolerance for this
• SO have T-cells that can recognise peptides from Tyrosinase

Tyrosinase is invovled in skin pigmentation
• in melanoma treatment, the t-cells target cancer cells AND tyrosinase = loss of skin pigmentation (vitiligo)

22
Q

2 major obstacles in targeting TA auto-antigens for T-cell mediated immunotherapy of cancer?

A

(1) A.I response against normal tissues (as seen w. vitiligo in melanoma)
(2) Overcoming any immunological tolerance

23
Q

Explain (2) in regards to the obstacle of using TA-auto-antigens for T-cell mediated immunotherapy of cancer?

A

(2) Tumour-induced tolerance

 Normal tolerance means you can NOT use that antigen for immunotherapy

 Sometimes the tumour cells expressing the antigens can induce tolerance as they might not cause inflammation so the presentation of the antigens without co-stimulation could make the T-cells anergic and induce tolerance

24
Q

What are the approaches to Immunotherapy?

A

(1) Ab-based therapy
(2) Therapeutic vaccination
(3) Immune checkpoint blockade
(4) Adoptive transfer of immune cells
(5) Combinations of 1-4

25
Q

Explain (1) of Immunotherapy

A

Ab-based therapy (monoclonal)

‘Naked’ - DIRECT Ab
• e.g. Anti-HER2 Ab (Herceptin)

‘Conjugated’ - Ab + radioactive particle.drug

‘Bi-specific’ - multiple direct abs
• genetically engineered to combine 2 specificities

26
Q

Explain (2) of Immunotherapy

A

Therapeutic Cancer Vaccination

Only ONE FDA approved vaccine to treat cancer
• Provenge (prostate cancer)

Patients own WBC treated with a fusion protein (of PAP [prostatic acid phosphatase]) & the cytokine GM-CSF
• stimulates DC maturation
• enhances PAP-specific T-cell responses

27
Q

Explain (3) of Immunotherapy

A

Immune Checkpoint Blockade

Reduces/removes -VE regulatory controls of existing T-cell responses
• enhances the response already made against the patient’s OWN cancer

Targets:
o CTLA-4 - expressed on activated T-reg cells & binds to CD80/86 (co-stimulatory molecules of APCs)
o PD-1 - expressed on activated T-cells, binds to PD-L1/L2

28
Q

Examples of Immune checkpoint blockade drugs?

A
  1. Ipilimumab
    • anti-CDLA-4
  2. Nivolumab
    • anti-PD-1
29
Q

Explain how (4) of Immunotherapy works

A
  1. Remove tumours by surgery
  2. Extract the TILs = multiply no. of TILs = reinfuse TILs into patient

TILs genetically modified to express CAR
• making a new pathways to kill cells
• take variable bit of Ab and link to CD3-zeta cytoplasmic domain which signals to T-cell if binds to antigen

o TIL - tumour-infiltrating lymphocyte
o CAR - chimeric antigen receptor

30
Q

TSA vs. TAA?

A

TSA
• expressed via. onco-proteins
• are NOT normally found in the body

TAA
• NORMAL proteins
• aberrantly expressed by tumours

Year 2 - MCD Immunology (6 decks)

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