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Multiple factors involving chronic inflammation (inflammatory bowel disease, ulcerative colitis and Crohn’s disease) that may Lead to a polyp developing into colorectal cancer. Lymphocyte transformation, Expansion of transformed lymphocytes and then evasion of immune surveillance. Tumour suppressor genes are inactivated while oncogenes are activated.
Development of the lymphoid malignancy involve
At the molecular level, cancer arises when
Tumours Induction cont
Tumours induced by
Chemical carcinogens Cigarettes which contain polycyclic hydrocarbons Viruses and genetic derrangements in neoplastic transformations of human cancer. Tumour infiltrating leukocytes CD4+ T cells, CD8 T cells, NK cells, B lymphocytes Macrophages/dendritic cells)
Tumour immunity associated with
Receptors and differentiation antigens Specific and non-specific receptors expressed by tumour cells. Epidermal growth factor (EGF), a receptor demonstrated on solid tumours including Breast carcinoma, bladder carcinoma, lung carcinoma and melanoma.
Growth Factor Receptors
Receptors for platelet growth factors, fibroblast growth factors and insulin growth factors expressed on Cancer cells without exhibiting tumour specificity Common acute lymphoblastic leukaemia antigen (CALLA or DC10) detected on melanoma and glioma cells.
Various stages of foetal development and tumours Characterized by production of oncofoetal or onchodevelopment proteins involved in cell-cell interactions. Carcinoembryonic antigen (CEA)
Encoded by Ig gene superfamily molecules and expressed by foetal and human colon cells.
CEA forms include Neutral cell adhesion molecules Myelin associated glycoprotein and melanoma – associated antigens Germ cell tumours and hepatocellular carcinomas express
Embryonic antigens and other glycoproteins like alpha-fetoproteins.
Epstein Barr virus (EBV) infection associated with Induction of nasopharyngeal carcinoma and Burkitt’s lymphoma. Human papilloma viruses are implicated in the cervical cancer. Viral antigens (EBV specific surface antigens) Detected on the tumour cell membranes.
Tumours associated with low levels of class I MHC antigens and Reduced CD8+ T cell recognition and activation
Immune surveillance against tumours evidence Malignacy most common when immune function poorest at the extremes of age Malignancy rates increasing in patients with chronic immunosuppression ( congenital immunodeficiency, AIDS and transplant recipients) Tumours often infiltrated with Lymphocytes, macrophages and dendtritic cells and anti-tumour immune effector mechanisms.
NK Cell Mediated Suirvellance
NK cells spontaneously eliminate neoplastic cells by Antibody-independent and MHC-independent mechanisms without a requirement of prior sensitization. NK cells exposed to sensitive target cells degranulate leading to exocytosis. Target cells express low levels or absence of MHC antigens and thus activate NK cells. Cytolytic factors released include perforins, serine esterases and chondroitin sulphate.
NK Cell Activity cont
Major effector cytotoxic mechanisms
Perforin – mediated membrane damage,
NK cell cytotoxic factor (NKCF), TNF-α α, β and γ have anti-proliferative effects on tumours (melanomas). Activated NK cells
Lymphokine activated killer (LAK) effector cells against tumours predomonant
CD8 CTL triggered when target tumours cells Display antigens in association with class I MHC products. Cytotoxicity mediated by cytolytic factors (pore forming proteins and cytolysins) Lysis of tumour cells by FasL trigger of apoptosis (lung carcinoma) or by Direct exocytosis of granules containing perforin and granzymes.
CTL induce apoptic death through Granzyme-mediated pathways Triggers positive feedback loop that amplifies the T cell antitumour immune response.
Fig. 53: CD8+ T-cell Immunity Against Tumours. CD8+ T cells TCR recognize tumour antigen peptides on the surface of any host cell, in association with class I MHC molecules. T cell receptors bind to a triad of three proteins on the surface of target cells: MHC I molecules, β-2 microglobulin and short (9-10 amino acid) peptides on the surface of the MHC I molecule. MHC I molecules bind peptide fragments derived from proteolytically degraded tumour antigens or through neoplastic transformation. Small antigenic peptides are transported into the endoplasmic reticulum (ER), whre they associate with nascent MHC I molecules before being routed through the ER and displayed on the surface. Source: www.medscape.com/content/2004/00/46/77/467743/467743-fig.html
In ADCC usually IgG bound onto the tumour target
Provides the recognition site for Fcexpressing cytotoxic cells.
Killer (K) cells (subpopulation of NK cells) Express CD16 antigens. Activation through CD16 antigen Triggers K cells which subsequently kill antibody coated tumour cells by ADDC
Macrophage Mediated Damage
Chemoattraction of phagocytes by C5a, C3 and Subsequent activation of Fc-R mediated phagocytosis leads to Damage of tumours opsonized by antibodies. Activated macrophages destroy tumour cells. Macrophages cytotoxic towards tumour cells by Reactive oxygen intermediates contribute to the macrophage associated damage of tumours. Tumouricidal activities discriminate between normal and neoplastic cells.
Privileged sites Tumours in sites eg the eyes and central nervous system inaccessible to potent immune attack. Tolerance induction through Re-expression of embryonic tumour associated antigens (TAAg) or Expression of novel antigens on normal cells.
TGF-β and prostaglandin E2 generated Inhibit immune response and local anergy or tolerance in tumour specific CTLs Associated with growth of
Colorectal carcinoma Prostate adenocarcinoma and glioblastoma.
Tumour Evasion cont
Reduced immunogenicity Non-immunogenic tumours appear gradually and persist while immunogenic ones emerge rapidly and are eliminated faster. Down-regulation of MHC antigens contributes to reduced immunogenicity and Susequent promotion of tumour growth and proliferaton.
Antibody Mediated Modulation
Surface membrance changes/capping on the tumour cells. Antibodies form immune complexes with the surface tumour associated antigens which Move towards the edges or periphery of the tumour cells involving the “capping” phenomenon. Subsequently either endocytosed or shed off.
Interferance With Antigen Presentation
Through Down regulation of MHC Class I molecules leads To protection of neoplastic cells against CTL killing.
Expression of FasL Molecules
Binding of ligand (FasL) or anti-Fas antibodies to Fas leads to apoptosis of the Fas bearing cells. Expression of FasL molecules on neoplastic cells (non-lymphoid malignancies) Induces apoptosis of Fas expressing T cells that infiltrate the tumours and then escape CTL damage.
Expression of HLA-G Molecules
By tumour melanoma cells, glioma and skin malignancies Protects against NK cell cytoxicity. Secretion of soluble HLA molecules and soluble FasL (sFasL) Induces apoptosis of T cell expressing Fas and NK in circulation Render them ineffective against a wide variety of tumours.
Blocking factors (immune complexes) Mask surface tumour antigens or Prevent cytotoxic cells or cytotoxic antibodies. Immunosuppressive factors (prostaglandins and alpha-fetoproteins) Promote tumour growth.
Immunosuppression in Pregnancy
Defective cellular mechanisms during pregnancy Exacerbate various transformed and neoplastic cells leading to Increase in the frequency of virus-induced tumours (Burkitt’s lymphoma, genital warts, mammary cancer, cervical carcinoma, hepatomas and adenomas.)
Tumour markers include Oncofoetal antigens Carcinoembryonic antigens Prostate specific antigens Hormones, enzymes, isoenzymes and other specific proteins Detection and characterization of tumour associated antigens of Clinical value in the diagnosis and treatment of various tumours.
Leukaemias and Lymphomas
Monoclonal cell markers valuable in Classification and identification of various leukaemais and lymphomas
Classification and Diagnosis of Leukemias and Lymphomas
Designation CD1 CD2 CD3 CD4 CD5 CD6 CD7 CD8 CD9 CD10 CD11b CD11B CD13 CD14 Description Thymocytes dendritic cell E-rosetting T cells T cell (Pan T) associated with TCR Helper/inducer T cells T cell (Pan T); some malignant B cells T cells (Pan T); some B cells T cells (Pan T); some AML cells Cytotoxic/suppressor T cells Most haematopoietic cells Early B cells, some T cells and granulocytes Granulo/monocytes, dendritic cells, NK cells Monocytes, hairy cells Granulocytes, monocytes Monocytes, dendritic cells, some B cells All Lymphoma LGL HCL histiocytic malignancy AML AML (M4 and M5)histiocytic disease T cell malignancy Diagnostic Value T cell malignancy
CD15 CD16 CD17 CD19 CD20 CD 21 CD22 CD23 CD24 CD25 CD30 CD33 CD34 CD38 CD45R
Monocytes, granulocytes R.S cells NK cells, some T cells granulocytes, monocytes Granulocytes, monocytes, thymocytes Early B cell, B specific B cells (Pan B), B specific Mature B cells, dendritic cells B cells (Pan B), B specific Activated B cells, dendritic cells B cells, granulocytes, monocytes Activated T and B cells, hairy cells Activated T and B cells, R-S cells Early myeloid cells Stem cells, lymphoid blasts Thymocytes, active lymphocytes Supp/induc/T cells, B cells
AML, Hodgkin’s disease LGL
ALL, lymphoma ALL, lymphoma, CLL
Lymphoma, Hodgkin’s diseases AML Acute leukemia AML(ML) T-ALL
Cell Marker SmIg Cytoplasmic (Cµ) TdT CD1 CD2 CD4 CD5 CD7 CD8 CD10 HLA-DR CD19 CD20 CD34
T-All 20%) + + + + + + + + +
Comon All ALL) (75%) + + + + + -
Pre-B-ALL (1520%) + + + + + +
B-ALL (5%) + + + + + +
Detection of CEA Useful in the diagnosis of Colorectal carcinoma and other malignancies like colitis, pancreatic, tumour like thyroid and breast cancer.
Specificity of CEA appears low and not of great value in tumour screening programmes.
Detection of AFP
AFP,a glycoprotein common in patients with Liver and germinal tumours and Serves as a marker of tumour progression. Synthesized and released in hepatocellular carcinomas and testicular teratomas. Detection of AFP by Double diffusion and countercurrent – immunoelectrophoresis Useful in the diagnosis, monitoring and detection of tumour recurrence.
Measurement of serum levels of prostate specific antigen (PSA) Widely used as a screening tool for prostate cancer. Elevated PSA levels due to Prostate cancer Benign prostate enlargement Inflammation and dependent on age and ethnicity Prostatitis and lower urinary tract symptoms (LUTS) and prostate cancer.
PSA Detection cont
PSA also detectable in Breast, lung and uterine cancer (not accurately a prostate specific antigen) Determination of PSA concentration Value in detecting metastatic or persistent disease
Major approaches involve Use of monoclonal derived antibodies and Recombinant DNA derived cytokines. Active immunotherapy strategies involve Use of cytokines and co-stimulators Tumour vaccines and non-specific stimulation
Transfer of cultured immune cells (adoptive immunotherapy) or antibodies with antitumour reactivity into the patients. BCG induces inflammation, local cytokine secretion, recruitment of T cells, NK cells and macrophages and appears to offer small benefits.
Use of Cytokines
IFN-α Stimulates cell mediated cytotoxicty, Direct antiproliferative activity and upregulates MHC class I antigens on tumours. IL-2 (principal stimulator of T cell growth) Activates anti-tumour T cells and NK cells with IFN-α synergistic antitumour effect.
Levamisole stimulates Th1 responses Clinical value not well documented. Dendritic cell (CD) therapy generates CDs pulsed with peptides of TAAg shown to Have limited benefits for nasopharyngeal carcinoma.
Involves Transfect of tumour cells with genes coding for stimulatory cytokines (IL-2, IL-12) Benefits not well established.
Lymphokine activated killer cells generated when NK cells activated by IL-2. Use of tumour-infiltrating lymphocytes expanded with IL-2 promising.
Involve Procurement of heat shock proteintumour antigen vaccines or Induction of heat shock proteins that stimulate protective immune responses.
Use of Monclonal Abs
Monoclonal antibodies used in inhibiting or killing of malignant cells. Serotherapy takes advantage of monoclonal antibodies coupled to drugs, toxins, immunostimulants and radionuclides.
Bioconjugates of antibody linked to cytokines (IFN, TNF and IL-2) used. Clinical trials using the antibody conjugates have demonstrated varied responses against Melanomas, osteosarcomas, neuroblastomas, T cell lymphomas and gastrointestinal malignancies.
Use of Cytokines
Highly purified cytokines infused into tumour patients. Use of recombinant IFN - α demonstrated a positive response against eg Hairy cell leukaemia, low grade non-Hodgkin’s lymphoma, chronic myeloid leukaemia, HIV related Kaposi’s sarcoma, renal cell cancer and malignant melanoma.
Continuous infusions appear to augment CTL activity in tumour bearing patients. Anti IL-2R (Tac) used to detect Lymphomas which constitutively express Tac proteins.
CPA response shown in
Malignant lymphomas, leukemias, multiple myeloma, sarcomas Carcinomas of the testis, breast, ovary and lung. Attributed to inhibition of CD8 suppressor T cells Precursors are more susceptible than effector CD8+ T cells and B cells.
CPA mediated immunoenhancing effects
Gene Replacement Therapy Molecular basis of cancer involves Activation of tumour suppressor genes Inactivation of dominant oncogenes.
Somatic cells in cancer patients altered through Gene transfer intended to modulate the expression of selected genes and Suppression of malignant oncogenes in cancer cells. Genetic modulation leads to Generation of cytotoxic effector mechanisms against tumours through Introduction of genes for cytokines into cancer cells or lymphocytes.
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