cellular & molecular immunologynjms.rutgers.edu/gsbs/olc/mci/prot/2009/gradimm09tumor.pdf ·...
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Cellular & Molecular Cellular & Molecular ImmunologyImmunology
Cancer and the Immune SystemCancer and the Immune System
Nicholas M. Ponzio, Ph.D.Nicholas M. Ponzio, Ph.D.Department of Pathology & Laboratory MedicineDepartment of Pathology & Laboratory Medicine
May 4, 2009May 4, 2009
Lecture Overview• Tumor “antigens” as targets of immune attack
• Potential host immune mechanisms that protect against development and growth of cancer cells
• Ways in which tumor cells circumvent or neutralize host immune mechanisms
• Immunotherapeutic strategies for treatment of cancer patients
a group of diseases characterized by uncontrolled growth and spread of abnormal cells
What is Cancer?What is Cancer?
Cancer FactoidsCancer Factoids
• Since 2000, nearly 10 million new cancer cases have been diagnosed
• More than 1.2 million Americans develop cancer each year
• A new cancer is diagnosed every 30 seconds in the United States
• Cancer is the second leading cause of death after heart disease in the United States
What causes cancer?What causes cancer?
DonDon’’t know the exact causes, but evidence t know the exact causes, but evidence suggests contributing factors include:suggests contributing factors include:
Genetic influences Genetic influences –– oncogenesoncogenes
Environmental influences Environmental influences –– (carcinogens) (carcinogens) found in tobacco products, industrial found in tobacco products, industrial pollutants, pesticides, fertilizers, etc.pollutants, pesticides, fertilizers, etc.
Infectious organisms Infectious organisms –– some viruses and some viruses and bacteria may be bacteria may be oncogeniconcogenic
Suppression of immune protective mechanismsSuppression of immune protective mechanisms
How do cancer cells differ from normal How do cancer cells differ from normal cells?cells?
Autonomous growth Autonomous growth –– failure to respond to failure to respond to regulatory growth controlsregulatory growth controls
Ability to break away from the original tumor mass Ability to break away from the original tumor mass and migrate/grow in other tissues and migrate/grow in other tissues –– Metastasis Metastasis
Expression of Expression of ““newnew”” molecules (cell surface or molecules (cell surface or intracellular) that are not present on normal cellsintracellular) that are not present on normal cells
These new molecules (antigens) are potential These new molecules (antigens) are potential targets for the immune responsetargets for the immune response
TumorTumor rejection is an immune responserejection is an immune response
Remove tumor
Fig 17Fig 17--22
Tumor Antigens
Table 17-1: Tumor Antigens
PSA; CD10 (ALL); Ig idiotypes (B lymphomas)
Differentiation Ag
Papilloma viruses (cervical Ca); EBNA-1 (EBV-assoc lymphomas); SV40 T antigen (rodent tumors)
MART (melanomas; normally expressed in melanocytes)
CEA (GI and other Ca; normal in liver & during inflammation); AFP (Alpha-fetoprotein)
Oncofetal antigens
Oncogenic viruses
Overexpressed normal genes
Ras mutations (~10% human Ca); Her2/neu (breast & other Ca)
Oncogenes & tumor suppressor genes
Examples of Human Tumor AgsAntigens From
Oncofetal Antigens
Carcinoembryonic Antigen; Alpha fetoprotein
Normal vs. malignant B cells
• Malignant transformation can occur at any stage of development
• Daughter cells within the malignant clone express many of the same surface molecules as their normal counterparts
• Malignant cells exhibit unregulated growth
CD10 on normal and malignant B cells
<10% of PBMC are CD10+
100% of cells within the malignant clone
are CD10+
MHC IMHC II
Flow cytometry and Fluorescence-Activated Cell Sorting (FACS)
Immunophenotype of a patient with ???Chronic Lymphocytic (B cell) LymphomaCLL
Positive for:
CD5, CD20, CD19, CD23 (FcR);
kappa light chain
Negative for:
CD3; lambda light chain
Ig expression during B lymphocyte maturation
Electrophoresis patterns
Normal
Multiple Myeloma
Concept of Immunosurveillance(Lewis Thomas & McFarland Burnet; 1959)
Immune system functions to recognize and destroy clones of malignant cells before they develop into clinically relevant tumors. (T cells)
Based on this concept, one would expect a higher incidence of cancer in people who manifest T cell immunodeficiencies.
However, there is not an inordinately higher frequency of common cancers (breast, prostate, colon, lung) associated with T cell immunodeficiency states
Immunodeficiency (ID) and Cancer
KSHV-8Kaposi’s Sarcoma
Hepatitis BLiver
PapillomaCervical EBVB cell lymphoma
EBVB cell (Burkitt’s)lymphoma
Infectious Disease; Malaria
PapillomaSkin
Immuno-suppression for transplants or due to AIDS
EBVB cell lymphomaInherited Virus involvedType of CancerCause of ID
CR2 (CD21) = EBV Receptor
Potential Host Immune Mechanisms Against the Development of Cancer
• Anti-tumor antibodies
• Tumor-specific Cytotoxic T Lymphocytes (CTL)
• Natural Killer (NK) cells (resting or activated)
• Activated Macrophages
Potential Host Immune Mechanisms: Antibody response against tumor antigens
Potential Host Immune Mechanisms: Stimulation of tumor specific Cytotoxic T Lymphocytes (CTL)
Fig 17Fig 17--33
Potential Host Immune Mechanisms: Resting and cytokine activated NK cells
MHC I
MHC II
Potential Host Immune Mechanisms: Resting and cytokine activated macrophages
ADCC Effector Cells = NK cells, macrophages, eosinophils
Antibody Dependent Cell-mediated Cytotoxicity (ADCC)
Paradox: Tumor growth can occur in spite of immune reactivity
Genetic FactorsInnate & Adaptive
Immunity
Tumor
Escape
Mechanisms
Tumor escape mechanisms:Location Location Location
Tumor escape mechanisms:
Not all tumor antigens are created equal
(i.e., equally immunogenic)
Tumor Cell
MHC molecules present peptide antigens
Fig 17Fig 17--4: Tumor Escape 4: Tumor Escape MechanismsMechanisms
Tumor escape mechanisms:Failure to express co-stimulatory molecules
The most common cancers (breast, prostate, lung, colon) do not express co-stimulatory
molecules
The major goals of immunotherapy:The major goals of immunotherapy:
•• to identify tumor antigensto identify tumor antigens
•• to stimulate the patientto stimulate the patient’’s own immune system s own immune system to recognize antigens on tumor cells and mount to recognize antigens on tumor cells and mount effective mechanisms to destroy the tumor cells effective mechanisms to destroy the tumor cells
•• to be used with other forms of treatment to seekto be used with other forms of treatment to seekout and destroy tumor cells at metastatic sitesout and destroy tumor cells at metastatic sites
•• to be effective with minimal side effectsto be effective with minimal side effects
Immunotherapy Against Cancer
Antibodies coupled to drugs, toxins, radioisotopes; CTL
Specific
CytokinesNon-specificPassive
Tumor vaccinesSpecificBCG; C. parvumNon-specific
Active
Active immunotherapy requires the recipient to respond to the agent being administered
Table 17-2: Tumor Vaccines
Various carcinomasDC + tumor Ag gene
Melanoma; Renal CaHeat Shock Protein
MelanomaLysates
MelanomaAdeno or Vacciniawith tumor Ag
Viral Vectors
MelanomaImm w tumor Ag encoding plasmids
DNA Vaccines
Melanoma; NHL; ProstateDC + tumor AgAPC-based Vaccines
MelanomaMelanoma AntigenPurified tumor antigen
Melanoma; Colon CaCells Killed tumor vaccine
Clinical TrialsPreparationType
Fig 17Fig 17--5: Tumor Vaccines5: Tumor Vaccines
Table 17-4: Systemic Cytokine Therapy for Tumors
Abnormal liver functionPhase I Toxicity; Melanoma and others
Septic Shock Syndrome
Melanoma; Sarcoma
Bone painRoutine use to promote BM recovery in patients
GM-CSF
Fever; abnormal liver; CNS toxicicty; hypotension
Renal (no benefit seen)
IL-6
IL-12
TNF
Vascular leak; shock; pulmonary edema
Melanoma; Renal; Colon (<15% response)
IL-2ToxicityClinical TrialsCytokine
Fig 17Fig 17--6: Cytokine Gene6: Cytokine Gene--transfected Tumor Cellstransfected Tumor Cells
Table 17-5: mAbs for Cancer Therapy
Ovarian cancerMouse mAbCA-125
B cell lymphomaHumanized mouse mAb
B cell lymphomaHumanized mouse mAb
MelanomaHumanized mouse mAb
GD3 Ganglioside
GI and lung cancers
Humanized mouse mAb
CEA
CD10
CD20
Breast Ca (approved for clinical use)
Humanized mouse mAb
Her-2/NeuClinical TrialsForm of mAb usedSpecificity
B-Cell Lymphomas Express Several Antigens That Can Be Targeted
Adapted from Press. Semin Oncol. 1999;26:5(suppl 14):58.
HLA-DR (MHC II)
sIg
CD19
CD22
CD23
CD40CD80
CD20
CD20 Is Not Expressed on Stem Cells or Plasma Cells
Pluripotent stem cell
Lymphoid stem cell
Pre-B cell B cell Activated B cell
Plasma cell
Bone Marrow Blood, Lymph
Press. Semin Oncol. 1999;26:5(suppl 14):58.
CD20
BEXXAR: Characteristics
131131II
Tyrosine Tyrosine labellabel
TositumomabTositumomab(Murine IgG2a) (Murine IgG2a)
CD20 BindingCD20 Binding
γγ and and ββ--radiationradiation
Tumors can develop resistance to treatment
Adapted from Press. Semin Oncol. 1999;26:5(suppl 14):58.
HLA-DR (MHC II)
sIg
CD19
CD22
CD23
CD40CD80
CD20
Resistance to continued treatment
Downregulation or mutation of
surface molecules
Anti-CD20 mAb
Generation of tumor-specific CTL clones