Download - Cancer immunology
CAN YOU GIVE DEFINITIONS FOR FOLLOWING TERMS?
• CANCER?
• BENIGN AND MALIGNANT TUMOURS ?
• METASTASIS?
• CARCINOMA?
• SARCOMA?
• LEUKEMIA?
• CARCINOGENS?
• A tumor that is not capable of indefinite growth and does
not invade the healthy surrounding tissue extensively is benign.
• A tumor that continues to grow and becomes progressively invasive is malignant
• small clusters of cancerous cells dislodge from a tumor, invade the blood or lymphatic vessels, and are carried to other tissues, where they continue to proliferate. – metastasis
• carcinomas, tumors that arise from endodermal or ectodermal tissues such as skin or the epithelial lining of internal organs and glands
• sarcoma derived from mesodermal connective tissues such as bone and cartilage.
• Leukemia – abnormal proliferation of WBC
• Lymphoma tumors comes on spleen and lymph node
Malignant transformation of cells
• Normal cell in vitro transformed cells
Initiation& promotion is the steps in cancer development
Physical &chemical agents
These cells requires low anchorage dependence, decreased dependence of
growth factors ,and grow in density independent fashion like cancer cells
Malignant transformation can also be happens by viruses, its genome integrate to host DNA, oncogene in virus induce cancer
e.g. . Rous sarcoma virus v-src gene is responsible for cancer
Oncogenes (both viral and cellular) are derived from cellular genes that encode various growth-controlling proteins – Howard Temin
the conversion of a proto-oncogene into an oncogene appears in many cases to accompany a change in the level of expression of a normal growth controlling protein.
Oncogenes and cancer induction
• Cellular proliferation/ cell death
Imbalance
cancer
Balance is maintained by oncogenes and
tumor suppressor gene
Inappropriate expression of either a growth factor or its receptor can result
in uncontrolled proliferation
Tumors of immune system
• Solid tumor on bone marrow lymph nodes and thymus
• Include hodkins & non hodkins lymphoma
Lymphoma
• Proliferate as single cell
• Increased cell no. in blood or lymph
• Classified as acute and chronicLeukemia
Leukemia
CHRONIC
chronic
lymphocytic leukemia (CLL))
chronic myelogenous
leukemia (CML
ACUTE
Acute lymphocytic
leukemia (ALL));
Acute myelogenous
leukemia (AML
CHRONIC ACUTE
The chronic leukemia were much less aggressivedeveloped slowly as mild, barely symptomatic diseases.
The acute leukemia's appeared suddenly and progressedrapidly
Tend to arise in less mature cells, Arise in mature cells.
TUMOR ANTIGENSTSTA & TATA
• Tumor-specific antigens are unique to tumor cells and do not occur on normal cells in the body.
• Mutation creates new peptide - processing of it –MHCI presents it - Tcyt try to kill it
• Tumor-associated antigens are not unique to tumor cells and occur on also in normal cells in the body
Tumor antigens-4 categories
■ Antigens encoded by genes exclusively expressed by tumors
■ Antigens encoded by variant forms of normal genes that have been altered by mutation
■ Antigens normally expressed only at certain stages of differentiation or only by certain differentiation lineages
■ Antigens that are over expressed in particular tumors
THESE MUTANT TUMORS CELLS ARE DESIGNATED AS tum- VARIANTS
SOME CELLS ARE MUTATED AND ARE INCAPABLE OF GROWING IN TO A TUMOR IN SYNGENIC MICE
MOUSE TUMORIGENIC CELL LINE(tum+), GIVING RISE TO PROGRESSIVELYGROWING TUMORS & TREATED IN VITRO WITH A CHEMICAL
MUTAGEN
The TSTA specific CTLs destroy tum- tumor cells preventing tumor growth
When this variant cells are injected to a syngenic mice , the unique TSTA are recognized by specific CTLS
Most of this variants have been shown to TSTA not expressed by original TSTA variants
Virally induced tumor antigen
In contrast to chemically induced tumors , virally induced tumor express tumor antigens shared by all tumors induced by the same virus
TATA
• It is expressed on fetal and tumor cells not in normal cells – oncofetal tumor antigens
• E.g. Alpha-fetoprotein (AFP) found in liver cancer cells and fetal cells as milligram and nanogram in normal cells
• Carcinoembryonic antigen (CEA). – colorectal cancer cells
• the presence of these oncofetal antigens is not diagnostic of tumors but rather serves to monitor tumor growth.
( a patient has had surgery to remove a colorectal carcinoma,CEA levels are monitored after surgery. An increase in the CEA level is an indication of resumed tumor growth.)
Oncogene proteins as tumor antigens
• human breast-cancer cells exhibit elevated expression of the oncogene-encoded Neuprotein, a growthfactor receptor, whereas normal adult cells express only trace amounts of Neu protein
TATAs on human melanoma
Oncofetal - MAGE 1 , MAGE 3, BAGE, GAGE 1 , GAGE 2ONCOGENE PROTEINS –MART 1, gp75, gp 100,Melan A
WHAT WILL EACH OF THESE CELLS DO TO GET SUCCESS IN THIS WAR?
CANCER CELL
• MHC EXPRESSION DECRESES
• ANTIGENIC MODULATION
• COSTIMULATORY SIGNALS DECRESES
• ANTIBODY MASKING
IMMUNE CELL
DETECTION
• BY MHC I EXPRESSION
• LIPID ASSYMMETRY
KILLING
• MACROPHAGES, KILLER (NK AND TC )
SIGNALLING
Immune response to tumors
• T cell mediated immunity
Tcyt provide effective anti tumor immunity together with
class I MHC molecules
The stimulation of TH cells activate Tcyt cells , once
activated then again co stimulation is not
needed• T H cell recognize tumor Tcyt cell destruct tumor
• CD40 on T cell amplify immune response, cytokines call
macrophages , dendritic cells
IMMUNE SURVIELLANCE THEORY – WHEN TUMOR CELLS ARISE CELLS OF THE BODY RECOGNISE THEN & ELIMINATE1900 , PAUL EHRLICH
• Cross priming / cross presentation
BY M.J BEVAN
THE ABILITY OF APC TO PRESENT ANTIGEN BY CLASSI MHC PATHWAY IS CALLED CROSS PRESENTATION
NK CELL & MACROPHAGE MEDIATED IMMUNITY
• NK cell – missing self hypothesis –it is not MHC restricted so it can detect & kill tumor cells that escape from Tcyt cells
• Antibody-Dependent Cell-Mediate Cytotoxicity (ADCC) is linked with NK cells
• NK cell Activity increases in presence of IL 2 (adoptive immunotherapy – LAK)
• CHEDIAK HIGASHI SYNDROME -
CANCERNK
• MACROPHAGE• NON MHC MEDIATED
• ADCC – WITH ANTIBODY
• DEGRADATION OF TUMOR IS DUE TO LYTIC ENZYMES & ROS
• TNF (TUMOR NECROSIS FACTOR)
INDUCES NECROSIS OF TUMOR , BY THROMBOSIS IN BLOOD VESSELS
RESULTING IN ISCHAEMATIC DEGRADATION OF TUMOR OR DIRECT APOPTOSIS
DOWN REGULATION CLASS I MHC MOLECULES
ADENO VIRUS – INHIBITTRANSCRIPTION OF CLASS I MHCHERPES SIMPLEX VIRUS – TAP INHIBITES
MODULATION OF TUMOR ANTIGEN
• IN PRESENCE OF SERUM ANTIBODY ANTIGEN DISAPPEARS
• ANTIGEN LOSS VARIANTS FORMED
• OBSERVED IN MICE WITH T CELL LEUKEMIA –TL ANTIGEN IS MODULATED IN PRESENCE OF ANTI TL ANTIBODY
LACK OF COSTIMULATORS LIKE B7 ON APC- CD28 ON T CELL NEEDED TCELL GET PARTIAL SIGNAL , it
is another reason
Antigen masking
Coating antigen with glycocalyx or fibrin
Tumor cells produce more glycocalyx (surfce carbohydate )
Sialic acid
Blocking of Tcyt response by antibodies
• Antibodies formed against a tumor bearing host may bind to tumor antigens effectively blocking epitopes from Tcyt cells
• Mediated by antibodies alone or by antigen antibody complex
• These complexes may bind with with NK cells or macrophages and inhibit ADCC
SUPPESSION OF ANTI TUMOR IMMUNE RESPONSES
• Transforming growth factor β inhibit effectorfunctions of NK , macrophages
• Fas ligand bind fas molecule on leukocytes –apoptotic death of leukocytes
Preventing inflammatory response by secreting IL 10, VEGF - dendritic cell inactivated
Cancer immunotherapy/ biologic therapy
Uses hosts own immune system to fight against cancer and its side effects
Active
• Host immunity should not significantly weakened
Passive
• Tumor specific antibodies and Tcyt administrated
Active immunotherapy
• Killed tumor cell to patient enhances his immunity by increasing T cell population increase
• Patient specific tumor antigens used
• MAGE , mutated p53 common tumor antigens – broad spectrum of activity
RECENT RESEARCH FINDINGSMHC- PEPTIDECOMPLEX EXTRACTED &TESTED WHICH PEPTIDE CREATES
MORE T CELL ACTIVATION
ANTIGEN INTRODUCTION IS THROUGH RECOMBINANT VIRAL OR
BACTERIAL AGENTS( STUDIED ON FELINE LEUKEMIA IN RATS & HERPES
LYMPHOMA IN CHICKS)
ANOTHER METHOD IS EXTRACT APC & INTEGRATE TUMOR ANTIGEN GENE INTO IT AND INTRODUCE
BACKTO HOST
• AUGMENTATION OF IMMUNE RESPONSE BY COSTIMULATORS AND CYTOKINES ETC TO INDUCE T CELLS PROLIFERATION
• COSTIMULATORS WAS STUDIED IN MICE TUMOR CELL INTEGRATING WITH B7 GENE–Tcyt ACTIVATED
• LIKE THIS GENES OF CYTOKINES IL2 IL4 GM-CSF
• SYSTEMIC CYTOKINE THERAPY – INJECTION OF PURE CYTOKINE+ CHEMOTHERAPY /ADOPTIVE CELLULAR THERAPY
• NK CELLS IN VITRO + IL -2 ALSO USES
IFNαTHERAPYEFFECTIVE IN RENALCARCINOMA,
LYMPHOMA
IT INCREASE CYTOLYTIC ACTIVITY OF NK AND MHC I EXPRESSION
TOXIC EFFECTS – FEVER, PULMONARY OEDEMA VASCULAR SHOCK
TNF α and β inhibit tumor induced angiogenesis there by reduced blood flow
And inhibiting tumor growth
Isolate dendritic cellCulture with GM- CSF etc Dendritic cell proliferates thenpriming with tumor antigen& re introduce to host
Isolate tumor cellAdd cytokine gene Re introduced to host
Tumor bearing hostUsing antigen presenting cells 2 methods
T cells stimulated Dendritic cell activated by GM-CSF from expanded tumor cells
ADJUVANT MEDIATED IMMUNITY BOOSTERS
• A number of adjuvants including the attenuated strains of mycobacterium boviscalled bacillus calmette guerin (BCG) & CORYNE BACTERIUM PARVUM have been used to booster immunity
• It activate macrophage, cytokines classII MHC , B7
• GENRERALISED INCRESE IN HUMORAL & CELL MEDIATED IMMUNITY
Adoptive cellular immunotherapy
• Transfer cultured immune cell for anti tumor activity
• Rosenberg - NK cell + IL 2 = LYMPHOKINE ACTIVATED CELL OR LAK CELL
• Chemotherapy +LAK mice has antitumor activity in mice
• research on humans is ongoing
• Side effects- vascular leak syndrome – migration of lymphoid cells and plasma from the peripheral blood vessels in to the tissue
• More effective tumor destruction
Tumor infiltrating lymphocytes
• Variation of previous technique
• TIL is extracted from the inflammatory infiltration around tumor
• With IL 2 expand in enormous no. in vitro
• Expanded for specific tumor recognition
• Reintroduce to host
• Eliminates tumor completely or partially
Monoclonal antibody• Intelligent way• Single antigen• EGFR on tumor cell receptor • Antibody from rat or rabbit bind with it• Breast cancer receptor is HER toxin is
herceptin• Fc part replaced by human antibody• +TOXIN - DIPTHERIA TOXIN & RICIN -GUIDED MISSILE THERAPY• CONJUCATED ANTIBODY – RADIOACTIVE
PARTICLES , TOXINS , CHEMICALS + ANTIBODY
• Rituximab is one of mab commonly used
HUMORAL IMMUNO THERAPY
FUTURE EXPECTATION
• VACCINATION research is on going e.g. HPV vaccine that have,
• low cost
• And Reach every where in the world