Tumor Immunology Prt 2 Flashcards
SERUM TUMOR MARKERS
Limitations
- Can be elevated in benign conditions
(endometriosis) and other malignancies
• Increase during pregnancy and menstruation
CANCER ANTIGEN 125 (CA 125)
Clinical Applications
• Screening, diagnosis, prognosis, and monitoring response to therapy in ovarian cancer
CANCER ANTIGEN 125 (CA 125)
Structure
• Large, heavily glycosylated, mucinlike protein
• Lacks sensitivity and specificity
CANCER ANTIGEN 125 (CA 125)
Limitations
• Elevated in colitis, diverticulitis, irritable bowel syndrome, and nonmalignant liver disease
• Cigarette smoking can cause an increase in CEA level to nearly twice that of nonsmokers
• Elevated in other cancers: breast, gastrointestinal tract, pancreas, and lung
CARCINOEMBRYONIC ANTIGEN (CEA)
Clinical Applications
• Mainly used for monitoring patients undergoing therapy for colorectal cancer
• Detected with an average of 5 months before clinical symptoms appear
• Sensitive indicator of liver metastasis
CARCINOEMBRYONIC ANTIGEN (CEA)
- First oncofetal antigen discovered in 1965 by Gold and Freedman
• Glycoprotein with molecular weight of 180,000 to 200,000
CARCINOEMBRYONIC ANTIGEN (CEA)
• Limitations
• Elevated in gonadal suppression caused by chemotherapy and do not necessarily indicate tumor recurrence
HUMAN CHORIONIC GONADOTROPIN (hCG)
- “pregnancy hormone”
• Synthesized by trophoblasts during pregnancy
• 45,000 MW glycoprotein with a (LH, FSH, TSH) and B subunits
• Associated with germ cell tumors (ovary and testes) and choriocarcinoma - Measures intact hCG or hCG B subunit
HUMAN CHORIONIC GONADOTROPIN (hCG)
• Limitations
• Elevated in benign prostatic hyperplasia (BPH) and prostatitis
PROSTATE-SPECIFIC ANTIGEN (PSA)
Clinical Application
- Widely used marker for prostate cancer screening and monitoring
• PSA values, in conjunction with histological observation of prostate biopsy tissue, can be used to predict the stage of prostate cancer
PROSTATE-SPECIFIC ANTIGEN (PSA)
- 28,000 MW glycoprotein produced by prostate epithelial
• First discovered in semen
PROSTATE-SPECIFIC ANTIGEN (PSA)
LABORATORY DETECTION OF TUMORS
LABORATORY METHODS
• Tumor Morphology (Gross and microscopic)
• Tumor Marker Detection (Immunohistochemistry or Automated
Immunoassays)
• Molecular Diagnostics (Genetic mutations)
• Main use: cancer screening and diagnosis
Laboratory methods
LABORATORY METHODS
- Tissue Processing
- Pathologists and histology labs process suspected tumor tissue through gross dissection and slide preparation. - Microscopic Analysis
- Slides are examined microscopically, often enhanced with tumor marker antibodies, special stains, and nucleic acid probes. - Diagnosis
• Final diagnosis requires considerable skill and is supplemented with clinical information and additional testing.
TUMOR MORPHOLOGY
LABORATORY METHODS
- Technique
- Uses labeled antibodies to detect tumor antigens in formalin-fixed or frozen tissue sections. - Process
• Involves applying primary and secondary antibodies, with visualization through light or fluorescent microscopy. - Application
- Effective for classifying tumors of uncertain origin and identifying specific markers for precise tumor classification.
IMMUNOHISTOCHEMISTRY
- Advantages
• Highly sensitive, automated, and relatively easy to use for measuring serum tumor markers. - Challenges
• Variability in antibody reagents, cross-reactivity issues, and potential for antigen excess leading to the high-dose hook effect. - Considerations
- Importance of consistent methods for patient monitoring and awareness of potential interferences from endogenous antibodies.
IMMUNOASSAYS FOR CIRCULATING TUMOR MARKERS
• Nucleic Acid Amplification Techniques (NAAT)
- Detect genetic mutations
• Fluorescent In-Situ Hybridization (FISH)
- for detecting chromosomal abnormalities and gene amplification.
• Microarrays
- Testing for panels of genetic markers and comparing gene expression levels.
• Next Generation Sequencing (NGS)
- comprehensive genetic analysis of tumors.
MOLECULAR TECHNIQUES IN CANCER DIAGNOSIS
• 2D Electrophoresis
- Separates proteins based on their isoelectric point and molecular weight, coupled with mass spectrometry for identification.
• Surface-Enhanced Laser Desorption/lonization Time-of-Flight (SELDI-TOF)
- mass spectrometry for protein analysis.
• Antibody Arrays
- Multiplex protein detection using antibody-coated beads and fluorescent labeling, analyzed by flow cytometry.
PROTEONOMICS IN CANCER RESEARCH
- immune system continually patrols the body for the presence of cancerous or precancerous cells and eliminates them before they become clinically evident
THEORY OF IMMUNOSURVEILLANCE
- 1950s F. Mactarlane Burnet and Lewis Thomas
THEORY OF IMMUNOSURVEILLANCE
High Cases of Cancer
transplant patients who received…
patients with ____diseases
after the age of___
immunosuppressive therapy
immunodeficiency
60
IMMUNE DEFENSES AGAINST TUMOR CELLS
INNATE IMMUNE RESPONSE
NK cells
Macrophages
Lymphokine-Activated Killer (LAK) Cells
• kill tumor cells without prior sensitization
• activated by cells lacking class I MHC molecules (a common trait in transformed cells)
• most effective against malignant cells in the bloodstream during the early stages of tumor development
NK Cells
• when activated by IFNy, they can kill tumor cells using mechanisms similar to those used against infectious organisms.
• produce TNF-a
Macrophages
IMMUNE DEFENSES AGAINST TUMOR CELLS
ADAPTIVE IMMUNE RESPONSE
Cytotoxic T Lymphocytes (CTLS)
T Helper Cells
Antibodies
• kill tumor cells through complement-mediated lysis or antibody-dependent
cellular cytotoxicity (ADCC), though their in vivo relevance is unclear.
Cytotoxic T Lymphocytes (CTLS)
ADAPTIVE IMMUNE RESPONSE
• secrete cytokines like IL-2 and IFNy, which enhance CTL development and NK
cell activity, and activate macrophages.
• T Helper Cells
• primary mediators of adaptive immunity against tumors
• activated by dendritic cells presenting tumor antigens
• use perforin and granzymes to induce apoptosis in tumor cells.
Cytotoxic T Lymphocytes (CTLS)
• secrete cytokines like IL-2 and IFNy, which enhance CTL development and NK
cell activity, and activate macrophages.
• T Helper Cells
• kill tumor cells through complement-mediated lysis or antibody-dependent
cellular cytotoxicity (ADCC), though their in vivo relevance is unclear.
Antibodies
IMMUNOEDITING AND TUMOR ESCAPE
Robust innate and adaptive immune responses kill most tumor cells
Tumor cells identified by antigen and MHC 1; induced to apoptosis by FAS ligand
Elimination phase
IMMUNOEDITING AND TUMOR ESCAPE
Immune system controls limited number of altered cells
Tumor cells dormant; begin to lose or mask identifying features
Equilibrium
IMMUNOEDITING AND TUMOR ESCAPE
Immune system suppressed; chronic inflammation promotes tumor growth
Tumor cells highly altered and more resistant to immune responses; apoptosis impaired
Escape
___________
To identify cancer in asymptomatic individuals in a population.
_________
To identify cancer in a particular patient.
Presence of the marker or an elevation of the marker above normal levels suggests the presence of the cancer.
_________
To predict the clinical outcome of a cancer patient and aid in therapeutic decision making.
An initial high concentration or an increasing level of the tumor marker over time indicates a worse prognosis.
________
To observe the response of a cancer patient to treatment.
Effective treatment is indicated by decreasing levels of the marker over time.
Screening
Diagnosis
Prognosis
Monitoring
___________
Antigens that are unique to a tumor or shared by tumors of the same type
___________
Antigens that are expressed in normal cells as well as tumor cells
___________
Expressed in many tumors but not in most normal tissues
____________
Expressed on immature cells of a particular lineage
__________
Found in higher levels on malignant cells than on normal cells
Tumor-specific antigens (TSAs)
Tumor-associated antigens (TAAs)
Shared TSAs (cancer/testis antigens)
Differentiation antigens
Overexpressed antigens
Burkitt lymphoma
Hodgkin lymphoma
Leiomyosarcomas
Post-transplant lymphoprolif-erative disease
Nasopharyngeal carcinoma
Epstein-Barr virus (EBV)
Hepatocellular carcinoma
Hepatitis B virus (HBV)
Hepatitis C virus (HCV)
Kaposi sarcoma
Human herpes virus 8
(HHV-8)
Cervical cancer
Other genital and anal cancers
Head and neck cancer
Human papilloma virus (HPV)
Adult T-cell leukemia or lymphoma
Human T-lymphotropic virus I (HTLV-1)
Merkel cell carcinoma (a type of skin cancer)
Merkel cell polyomavirus
