Cancer Flashcards
Immune Surveillance
- Immune system patrols for invading pathogens & cells that turn cancerous.
- Abnormal cells detected and removed by healthy immmune system
- Tumors can stimulate a protective specific, adpative immune response through tumor specific CD8+ T-cells
- Malignant cells find ways to escape immune surveillance
Immune Escape
Causes
- weak immunogenicity of the tumor due to its host origins
- rapid growth of the tumor overwhelms the immune system
- selective pressures on tumor cells promotes the development of mechanisms for evading host immune responses
Tumor-Specific Antigens
(TSAs)
Antigens that are uniquely expressed by tumor cells but not by normal cells.
Sometimes referred to as neoantigens.
Hypothetically, any of these Ag could be recognized by the immune system.
Tumor-Associated Antigens
(TAAs)
Normal cellular antigens expressed at higher levels by tumors as compared to normal cells or at different stages of development or differentiation.
- CA-125 and ovarian cancer
- PSA and prostate cancer
Biomarker
Protein or other component in the body that can be used as a measurable indicator to identify a disease state or assess the severity of the disease.
Cancer Biomarker
A biological factor which can be quantitatively measured to yield cancer-related patient information including:
cancer predisposition
early detection
monitoring cancerous growth
selection of treatment
overall prognosis
TAAs and TSAs can be used.
CTLs
CTLs
- Recognize tumor antigens presented by class I MHC.
- If tumor isn’t cleared, cells may upregulate CTLA-4 causing downgregulation of CTL response.
TH1 Cells
TH1 cells
- Tumor antigen specific
- Important in initiation of CTL function
- generate IFN-γ and TNF-α lead to classically activate macrophages
B-Cells
B-cells
- Formation of tumor specific antibodies
- Promote ADCC by NK cells and macrophages
- Promote complement-mediated tissue damage and inflammation
- Passive Ab administration has shown both a therapeutic effect & in some cases was linked to tumor progression
NK Cells
NK cells
- Down-regulation of MHC I by 50% of tumors
- Loss of MHC I ligand for inhibitory receptor of NK cells results in tumor killing and cytokine production
- Can kill tumor cells by ADCC
- Killing enhanced by IFN-γ, IL-12, and IL-15
Classically Activated
Macrophages
Classically activated macrophages
- Stimuated by IFN-γ
- Kill tumor cells via ADCC
- Recognize phospholipids ectopically expressed by malignant cells
- Release lysosomal components and cytokines
- Can lead to thrombosis in tumor blood vessels
- Results in inhibition of tumor growth
TH2 Cells
&
Alternatively Activated Macrophages
- TH2 Cells
- Produce IL-10 and IL-4
- Leads to alternatively activated macrophages
- TH2 Cells and alternatively activated macrophages contribute to a microenvironment high in TGF-β and vascular endothelial growth factor (VEGF)
- Downregulates the immune response
- Promote tumor angiogenesis
- Effects could contribute to tumor progression
Tumor Microenvironment
The unique cellular composition surrounding the tumor.
Pro-tumor
- TH2 cells and alternatively activated macrophages
- Generates an immunosuppresive environment
- Stimulation of Treg cells
- Generation of a low level of chronic inflammation
Anti-tumor
- TH1 cells and classically activated macrophages
- CTLs
- B-cells
- NK cells
Tumor
Decreased Immunogenicity
- Derived from host cells
- Do not expresses PAMPs
- Attenuates the anti-tumor innate immune reponse
- Decreased adaptive immune response
- High rates of heritable somatic changes due to high mitotic index and genome instability
- Mutations which result in decreased immunogenicity of tumor cells have selective advantage
- Antigenic modulation
- Low levels of MHC Class I expression
- Decreased expression of adhesion molecules
- Proteolytic shedding of MIC
- MIC molecules are a stress-induced “alterer” molecule that can bind to the NK cell activating receptor (NKG2D)
- Without activating receptor, NK cells fail to get stimulatory signal
- Lack of MHC I will no longer trigger killing
-
Blocking antibodies
- Anti-tumor antibodies bound to tumor antigens inhibit CTL function and may inhibit ADCC by NK cells
Tumor
Treated as Self
- Tolerogenic state can be induced by:
- Failure to induce a robust “danger signal”
- Poor innate immune response
- Prolonged antigenic exposure
- The “danger signal” results in increased B7 and MHC class I & II
- Allows the effective stimulation and activation of naive T cells
- If naive T cells encounter tumor antigens without co-stimulation, the tumor specific T-cell could be anergized as part of peripheral tolerance.
- T-cell activation in the absence of a “danger signal” is likely to result in tumor specific T-reg cells
- If tumor celsl are not promptly eliminated, tumor antigen specific T-cells can be downregulated by AICD (activation induced cell death) and CTLA-4 up regulation.