Bihong Zhao, M.D, Ph.D Department of Pathology 04-28-2009
Is tumor self or non-self?
How are tumor antigens generated? What are they?
How does immune system respond?
Introduction Tumor Antigens/Categories of Tumor Antigens Effectors Mechanisms in Tumor Immunity Limitations of the Effectiveness of The Immune Response Against Tumors Immunodiagnosis Tumor Immunoprophylaxis Immunotherapy
Deaths and percentage of total deaths for the 10 leading causes of death, by sex: United States, 2004 Causes of Death Male Female Rank Death Percentage of Death Rank Death Percentage of Death All causes 1,181,668 100 1,215,947 100 Diseases of heart 1 321,973 27.2 1 330,513 27.2 Malignant neoplasms 2 286,830 24.3 2 267,058 22.0 By Centers for Diseases Control and Prevention
#1 cause of death
#1 cause of death By Centers for Diseases Control and Prevention
Multiple step process Both spatially and temporally Happens all the time, in different locations Accumulation of multiple genetic alterations Deletion Insertions Point mutations Loss of heterozygosity (LOH) Chromosomal translocation
Example: Breast cancer. So different from individual to individual, in course, cause and manifestation
A physiologic function of the immune system Recognize and destroy clones of transformed cells before they grow into tumors and to kill tumors after they are formed Proposed by Mac Burnet in the 1950 s (1960 Nobel Prize in Physiology and Medicine) We all have cancerous cells that arise all the time. However, our body is able to control these events.
Common criteria for antigens: 1. Foreignness 2. High molecular weight 3. Chemical complexity 4. Degradability with the ability to interact with host MHC antigens
Developmental Differentiation Mutation Integrated Viral gene products
CML (Chronic myelogenous leukemia) Aka. Philadelphia chromosome t(9;22)(q34;q11) FISH Generation of a chimeric protein with dysfunctional properties Tyrosine kinase inhibitor treatments (such as imatinib and sunitinib)
Transcription factor Important in regulates The cell cycle DNA repair Apoptosis Tumor suppressor "the guardian of the genome, "the guardian angel gene," "master watchman, Molecule of the year (1993)
Relatively easy to develop mutations in p53
Li-Fraumeni syndrome. More than 50 percent of tumors contain a mutations or deletions of the TP53 gene. Restoring endogenous p53 function holds a lot of promise
Proto-oncogenes (c-onc) A normal gene that functions Growth factor receptors Signal transducers Become an oncogene Mutations Increased expression Chief mechanisms Chromosomal translocation Point mutation Gene amplification Viral infection
Kirsten rat sarcoma viral oncogene Proto-Oncogenes activated by gene rearrangement, point mutation, or gene amplification
AIDs: Increase in cancer indicence Lymphoma lymphocytes Carcinoma epithelial origin Sarcoma - connective tissue Table 19.3 Listed malignant neoplasms in immune deficient patients
Innate immune system Response is non-specific Exposure leads to immediate maximal response Cell-mediated and humoral components No immunological memory Found in nearly all forms of life Adaptive immune system Pathogen and antigen specific response Lag time between exposure and maximal response Cell-mediated and humoral components Exposure leads to immunological memory Found only in jawed vertebrates
Histological Evidence for Lymphocytic Activity in Cancer Invasive Squamous cell carcinoma ->
Professional APCs. Dendritic cells Macrophages B-cells Non-professional APCs Fibroblasts (skin) Thyroid epithelial cells Glial cells (brain) Pancreatic beta cells Vascular endothelial cells
APC Nu cle us Tumor antigens Class I HMC APC Nucleus Tumor antigens Class II HMC CD8 T-cell receptor CD4 Cytotoxic T cells (CD4+) T-cell receptor IL-2 and IFN-γ Cytotoxic T cells (CD8+)
The principal mechanism of tumor immunity is killing of tumor cells by CD8+ CTLs
Without sensitization Without MHC restriction Lyse a variety of target cells Have receptors for the Fc region of IgG Secrete tumor necrosis factor-α (TNF-α) LAK cells also play a role Cytokine activated killers. TILs.
IgM and IgG In the presence of complement Effective against leukemia and lymphoma Reducing metastases Ineffective in a solid tumor
FIGURE 19.1. Three phases of cancer immunoediting: elimination, equilibrium, and escape. (Adapted from GP Dunn, LJ Old, and RD Schreiber (2007): Immunity 21:137.)
Downregulate Class I or class II MHC molecule expression Lose expressions of antigens that elicit immune responses Fail to express co-stimulators The products of tumor cells may suppress antitumor immune responses
PSA CA-125 CD199 α-afp CEA
Immunohistochemical (IHC) Stain
Antibodies against antigens specific to tumor cells Carcinoma: p53 Prostatic adenocarcinoma: Racemase Liver: Hepar-1 Antibodies against tissue specific antigens Lung and Thyroid: TTF-1 Prostatic adenocarcinoma: PSA Neuroendocrine: Chromogranin, Synaptophysin
Prostate Tissue
No need to memorize table in syllabus (p285)
Estimated new cases and deaths from cervical (uterine cervix) cancer in the United States in 2008: New cases: 11,070 (invasive cancer) Deaths: 3,870 (1/3) Once the most common cause of death
Gardasil (cervical cancer) Produced by Merck Pharmaceuticals Approved by the FDA on June 8, 2006 Females 9-26 years old Is being tested for its effectiveness in other age groups and in combination with other vaccines Ineffective for treating women with pre-existing HPV infections (August 15, 2007)
Produced by GlaxoSmithKline In Phase III clinical trials HPV types 16 and 18 Contains chemicals designed to increase the immune response More than 18,000 women internationally between the ages of 15 and 25 Found a 92 % efficacy rate against new infection and 100 % protection against persistent HPV infection
Trastuzumab is approved by the Food and Drug Administration (FDA) First humanized antibody Target and block the function of HER2 protein over-expression Her-2/Neu positive +/- metastasized
Gleevec is a unique treatment for certain forms of cancer Philadelphia chromosome positive chronic myeloid leukemia (Ph+ CML) and Another cancer protein, called Kit, that is the suspected cause of gastrointestinal stromal tumor (GIST)
First antibody approved for immunotherapy in non-hodgkin's B-cell lymphoma and other B- cell lymphoproliferative disorders Efficacy of Rituxan treatment has been reported in nonmalignant autoimmune diseases such as rheumatoid arthritis Crosslinking of CD20 molecules by Rituxan induces therapeutic B-cell depletion
Nonspecific stimulation of the immune system Augmentation of host immunity with cytokines and co-stimulators
Tumor antigens Effector mechanisms in tumor immunity: Cytotoxic T lymphocytes Immuno-diagnosis Immunoprophylaxis/Immunotherapy