Tumour Immunology Flashcards
Example for immune surveillance
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
What 3 things does the ‘breast cancer case’ teach us
- Some tumours can express antigens normally absent from (or not detectable in) corresponding normal tissues
- The IS can detect & launch an attack on the abnormally expressed antigens/tumours
- In certain cases, this may result in A.I destruction of normal somatic tissues
Circumstantial evidence for immune control of tumours?
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 *
Explain the Cancer-Immunity cycle
- Cancer cells release cancer-specific antigens
- APCs take up the cancer antigens
- APCs prime the T-cells in the lymph nodes to the antigens
- T-cells migrate to tumour (CTLs)
- T-cells infiltrate tumour
• TIL = Tumour Infiltrating Lymphocytes - T-cells recognise tumour
- 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
Explain the cancer pathogenesis - the tumour growth
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
Summary of requirements for activation of an adaptive anti-tumour I.R?
- Local inflammation in tumour
2. Expression and recognition of tumour antigens
What are the potential problems in Immune Surveillance of cancer?
- It takes a while for the tumour to cause LOCAL INFLAMMATION
- Antigenic differences between the NORMAL vs. TUMOUR cells can be very subtle
• HENCE hard to pick up on by the APCs
What can we therefore do if the above condition for Immune Surveillance of cancer is NOT met?
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
How is the I.R to viruses similar to that of tumours?
T-cells can detect the health of the inside of the cell
• via. MHC molecule functions
• most tumour antigens are CYTOSOLIC antigens
What can tumour-specific antigens be separated into?
- Viral proteins
• that cause cancers - Mutated cellular proteins
Explain the cancers of viral origins
(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
Explain HPV and cervical cancer
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.
Name of vaccination against HPV?
Gardasil 9
Explain TAA
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
Examples of TAAs?
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
Specific examples of TAAs?
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)
Example of molecule that be considered BOTH Tumour Associated & Tumour Specific Antigen?
p53
- TAA - when it is OVEREXPRESSED
- TSA - when it becomes MUTATED
Why is Tolerance an issue in cancer immunotherapy
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
How can tolerance be used in immunotherapy?
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
Explain the issue with Immunotherapy in regards to TAA and AI
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
Explain an example of TAA and A.I problems
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)
2 major obstacles in targeting TA auto-antigens for T-cell mediated immunotherapy of cancer?
(1) A.I response against normal tissues (as seen w. vitiligo in melanoma)
(2) Overcoming any immunological tolerance
Explain (2) in regards to the obstacle of using TA-auto-antigens for T-cell mediated immunotherapy of cancer?
(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
What are the approaches to Immunotherapy?
(1) Ab-based therapy
(2) Therapeutic vaccination
(3) Immune checkpoint blockade
(4) Adoptive transfer of immune cells
(5) Combinations of 1-4
