- Using examples, enumerate the different classes of tumour antigens which are the targets of human immune response
- Products of passenger mutations (diverse mutated genes)
- Products of passenger mutations (mutations which play no role in tumorigenesis). May stimulate an adaptive immune response.
- Products of driver mutations (oncogenes or mutated tumour suppressor genes)
- Products of genes that are involved in tumorigenesis
- Example: BRCA1, BRCA2 in breast cancer and Ovarian Cancer
- Products of genes that are involved in tumorigenesis
- Aberrantly expressed proteins
- Normal, unmutated proteins whose expression is dysregulated in the tumour. Their aberrant expression is enough to make them immunogenic.
- Examples: CEA in colorectal adenocarcinoma
- Viral antigens
- Antigens produced by tumours driven by oncogenic viruses
- Example: HPV E6 and E7 in cervical carcinoma
- Oncofetal
- Antigens expressed in fetal tissues and in cancerous somatic cells
- Example: CEA in colorectal adenocarcinoma
- Oncoviral
- Antigens encoded by oncogenic viruses
- Example: HPV E6 and E7 in cervical carcinoma
- Mutated
- Antigens expressed by cancer as a result of genetic mutation or alterations in transcription (amplification)
- Example: BRCA1 and BRCA2 in breast and ovarian carcinoma
- Overexpressed/ accumulated
- Antigens expressed by both normal and neoplastic tissue with the level of expression highly elevated in neoplasia
- Example: HER2/Neu in breast cancer, BING-4 in melanoma
- Cancer-testis
- Antigens expressed only by cancer cells and adult reproductive tissues such as testis and placenta
- Lineage-restricted
- Antigens expressed largely by a single cancer histiotype
- Example: PSA in prostate adenocarcinoma, Melan-A/MART-1 in melanoma
- Post-translationaly altered
- Antigens whose altered glycosylation is tumour-associated
- Example;: MUC1 in Ductal adenocarcinoma and Renal cell carcinoma
- Idiotypic
- A specific “clonotype” of highly polymorphic genes expressed tumour cells
- Example: Monoclonal kappa or lambda light chains in Multiple Myeloma, Monoclonal TCR in T cell lymphoma
- Products of passenger mutations (diverse mutated genes)
- Briefly describe the human immune response to tumours
- Macrophages
- Cancer cells and stromal cells produce chemokines (CSF-1, CCL2, CCL3) → recruitment of monocytes and resident macrophages
- M1 macrophage (anti-tumor)
- Phagocytosis
- Intracellular destruction of apoptotic cells and waste products)
- Production of inflammatory cytokines
- Antigen precentation via MHCII to CD4+ T-cells, and MHCI to CD8+ T-cells
- M2 macrophage (Pro-tumor)
- Anti-apoptotic, stimulates proliferation and inflammation (TNF and NF-KB signalling)
- Angiogenesis (IL-17, IL-23, FGF, VEGF)
- Suppression of immune response (TGF-B, IL-10)
- Dendritic Cells
- Antigen presentation via MHCI to CD8+ T-cell and MHCII to CD4+ T-cell
- Cytokine production and initiation of inflammation
- Natural Killer Cells
- Cytotoxic activity (perforin and granzyme)
- Activate macrophages (IFN-y)
- Lyse MHC I negative tumor cells
- Cytotoxic T cells
- Antigen recognition displayed on MHC I by TCR on CTLs
- Cytotoxicity (Perforin, Granzyme)
- Apoptosis (Fas ligand binding to FASDR CD95)
- Humoral immunity (B-cells and antibodies)
- Alters function of antigenic targets on tumor cells
- Opsonize tumor cellls for the presentation of tumor antigens by DCs
- Antibody bound tumor cells activate complement cascade
- Contribute to NK cell mediated tumor killing via antibody-dependent cell-mediated cytotoxicity
- Macrophages
- Describe 5 mechanisms of immune evasion by tumours
- Low antigenicity and or antigen loss by tumors
- Elicit little inflammation and co-stimulation
- Express few non-self antigens
- Antigen loss variants – stop expressing antigens targeted by immune response
- Non-Expression of MHC 1 molecules
- Evade CD8+ cytotoxic T cells
- NK cells kill MHC I negative Tumors
- Production of immunosuppressive cytokines
- Some tumors secrete TGF-B and IL-10
- Some tumor induce Treg response
- Inhibition of T cell activation
- Tumors express PD-1 and CTLA4
- Tumors induce low levels of B7 costimulators on APCs
- Net result is reduced T cell activation upon recognition of tumor antigens
- Induction of Treg activity
- Treg activation suppresses antitumor immune response
- Rapid growth
- Rapid growth of tumor outstrips the immune defense
- Low antigenicity and or antigen loss by tumors
- Describe any 4 immunotherapeutic strategies against tumours
- Passive
- Antibody therapy
- Rituximab: targets CD20 on B-cell NHL, triggering Ab mediated cell cytotoxicity
- Alemtuzumab: targets CD52 on CLL
- Trastuzumab (Herceptin): Targets Her2/Neu in breast cancer
- Cetuximab: Targets EGFR on stage IV colorectal cancer, Head and neck cancers
- Antibody therapy
- Adaptive cellular therapy
- CTLs isolated from blood or tumor infiltrates are expanded in vitro culture and reintroduced to destroy tumor cells
- Chimeric antigen receptors
- Chimeric antigen receptors that recognize tumor antigens are genetically introduced in vitro and transferred back into the patient
- Active
- Vaccination
- HPV vaccine: Prevents cervical cancer
- Checkpoint blockade
- Antibodies that block CTLA4: Melanoma (2011)
- Antibodies that block PD-1 or its ligan PD-1L: anti-PD1 (2014)
- Cytokine therapy
- IL-2
- IFN-a
- IFN-Y
- Vaccination
- Passive
