Tumour Immunology and Immunotherapy of Cancer Flashcards
What evidence is the for immune surveillance?
Patient previously healthy developed vertigo, unintelligible speech and ataxia -> diagnosed with breast cancer
- Paraneoplastic cerebellar degeneration (PCD)
Tumour produced CDR2 which the body made antibodies against but these are also found on cerebellar purkinje cells neurones and so she has brain degeneration
*CDR2 – Cerebellar Degeneration-Related antigen 2
- some tumours can express antigens normally absent (or in immunologically privileged sites) in normal human tissue
- The immune system can detect and launch an attack on the abnormally expressed antigens/tumours
- In some cases, this may result in an auto-immune destruction of normal human tissue
What is 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
What is needed to activate an adaptive anti-tumour immune response?
- local inflammation
- expression and recognition of tumour antigens
What are the problems with immune surveillance of cancer?
- It takes a while for a tumour to cause local inflammation
2. Antigenic differences between normal and tumour cells can be very subtle and hard to pick up on by the APCs
What are some similarities between immune response to tumors and immune response to viruses?
T-cells can detect the health of the inside of the cell
- Via functions of MHC molecules
- Most tumour antigens are cytosolic antigens
Tumour-specific antigens can be separated into:
- Viral protein – that cause cancers
- Mutated cellular proteins
What are some opportunistic malignancies?
due to immunosuppression:
- EBV+ Lymphoma – post-transplant immunosuppression
- HHV8+ Kaposi’s sarcoma – HIV individuals
What are some cancers of viral origin that occur in immunocompetent individuals?
- HTLV1-associated leukaemia/lymphoma
- HBV- and HCV-associated hepatocellular carcinoma
- HPV+ genital tumours.
What induces and maintains cervical cancer?
E6 and E7 intracellular oncoproteins of HPV
What are tumour associated antigens?
derive from NORMAL cellular proteins which are aberrantly expressed – NOT mutated!
Because they are normal self-proteins, for an immune response to occur, tolerance may need to be overcome
What are some examples of TAAs?
- HER2 – Human Epidermal Growth Factor Receptor 2 – overexpressed in some breast cancers
- MUC-1 (Mucin-1) – membrane-associated glycoprotein overexpressed in many cancers
- CEA (Carcinoembryonic antigen) – normally only expressed in foetal/embryo, but overexpressed in cancers
- Prostate antigens – PSA (prostate-specific antigen), PSMA (prostate-specific membrane antigen), PAP (prostatic acid phosphatase
What causes central tolerance?
negative selection in the thymus
Why is there vitiligo in treatment of melanoma?
tyrosinase is a differentiation-type antigen
Lots of people have poor tolerance of this Tyrosinase and so lots of people have T-cells that can recognise peptides from Tyrosinase
Tyrosinase is involved in skin pigmentation
In treatment of melanoma, the t-cells target the cancer cells and the Tyrosinase and so there is a loss of skin pigmentation – vitiligo
What are the major problems in targeting tumour-associated auto-antigens for T-cell mediated immunotherapy?
Auto-immune responses against normal tissues (as seen above with vitiligo in melanoma)
Overcoming any immunological tolerance:
- Normal tolerance means you cannot 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 some approaches of immunotherapy?
- Antibody-based therapy
- Therapeutic vaccination
- Immune checkpoint blockade
- Adoptive transfer of immune cells
- Combinations of the above (1) (4)
What are the types of antibody-based therapy?
(monoclonal)
- “Naked” – direct antibody – e.g. Anti-HER2 antibody (Herceptin)
- “Conjugated” antibody + radioactive-particle/drug – radioactive particles (e.g. anti-CD20 linked to yttrium-90 (Zevalin)), drugs (e.g. anti-HER2 linked to cytotoxic drugs (Kadcyla))
- “Bi-specific” antibodies – multiple direct antibodies – genetically engineered to combine 2 specificities – e.g. anti-CD3 and anti-CD19
