Tumor Immunology PDF

Tumor Immunology Copyright ©2021 F.A. Davis Company  Chapter Overview § Tumor biology § Tumor an7gens § Clinically relevant tumor markers § Laboratory tests for tumors § Immune defenses against tumors § Immun...

Tumor Immunology Copyright ©2021 F.A. Davis Company  Chapter Overview § Tumor biology § Tumor an7gens § Clinically relevant tumor markers § Laboratory tests for tumors § Immune defenses against tumors § Immunoedi7ng and tumor escape § Immunotherapy Copyright ©2021 F.A. Davis Company  Learning Objec7ves A"er finishing this chapter, student should be able to: § Compare the characteris7cs of benign and malignant tumors. § Define and give examples of proto-oncogenes. § Describe the role of oncogenes § Describe the characteris7cs of the major body defenses against cancer. § Iden7fy and discuss the characteris7cs of tumor markers. § Discuss what’s new in cancer diagnos7c tes7ng. Copyright ©2021 F.A. Davis Company  Introduc7on to Tumor Biology § Tumor (neoplasm) = an abnormal cell mass Benign or malignant § Cancer = malignant tumor that can spread Caused by muta7ons in proto-oncogenes and tumor-suppressor genes Uncontrolled cell division and other characteris7cs Copyright ©2021 F.A. Davis Company  Defini7ons § Neoplasm: An abnormal mass of tissue that results from the uncontrolled growth of normal cell, even after the growth stimulus is removed § Benign tumor: Mild and nonprogressive tumor that pushes a side normal 7ssue, but does not invade it, as the tumor expands Copyright ©2021 F.A. Davis Company  Defini7ons (Con.) § Malignant tumor: Consis7ng of poorly differen7ated cells that grow rapidly and invade surrounding 7ssue, robbing the normal 7ssue of nutrients § Metasta7c tumor: Secondary tumor derived from a malignant primary tumor Copyright ©2021 F.A. Davis Company Copyright ©2021 F.A. Davis Company  Characteris7cs of Cancer Cells § Sustained prolifera7on § Altered metabolism § Resist death § Evasion of immune § Induce angiogenesis defenses § Immortality § Genomic instability § Invasion and metastasis § Accelerated growth in § Avoid suppressors of presence of inflamma7on cell growth Copyright ©2021 F.A. Davis Company  Tumor-Associated an7gens § In order for the immune system to react against a tumor, the laUer must have an7gens that are recognized as foreign. o Enzymes, receptors, membrane an7gens, etc § Most relevant are surface membrane molecules which might be antigenic or suppression of membrane proteins that are essential for immune recognition and activation Copyright ©2021 F.A. Davis Company  Tumor-Specific Pep7des § Intracelluar proteins expresses on tumor cells with MHC class I and II § This expression can be chemically induced Copyright ©2021 F.A. Davis Company  Virus-Induced Tumors § Tumors cause by viruses § Tumor cells express viral Ags. on their surfaces § Tumor cells are recognized as non-self by Immune System Copyright ©2021 F.A. Davis Company  Genome-Encoded Tumor An7gens § Oncogenes: if downregulated, the protein product can lead to tumor. § Proto-oncogenes: o Found in all nucleated cells (yeast to human) o Involved in cell growth o Altera7on in gene expression or protein structure may lead to abnormal cell growth Copyright ©2021 F.A. Davis Company  Oncofetal An7gens § Found on normal fetal cells § Produced in minute amounts a[er birth § Become expressed later a[er malignant transforma7on § Examples: o α-feto protein( AFP) o Carcinoembryonic an7gen (CEA) o ~90% of colorectal cancer have CEA (carcinoembryonic an7gen) Copyright ©2021 F.A. Davis Company  Immunity to Tumors Natural immunity: § Macrophage-mediated cytotoxicity: When macrophage come in contact with tumor cells § NK cells: 50% of tumors have muta7on that decrease MHC class I on their surfaces, facilitate killing via NK cells Copyright ©2021 F.A. Davis Company  Immunity to Tumors (Con.) Humoral-mediated immunity: § Antobodies: Can be produced to Ags. found on surfaces of tumor cells § Lysis of tumor cells via: o Complement ac7va7on o ADCC reac7ons involving NK, PMNs, and macrophages Copyright ©2021 F.A. Davis Company  Immunity to Tumors (Con.) T cell-mediated immunity: § Cytokines involved in tumor immunity: o IL-1 ac7vates T, B, and NK cells o TNFa destroys tumor cells o IFNg prduced by ac7vated T, B, and NK cells § CTLs : Can directly lyse tumor cells Copyright ©2021 F.A. Davis Company  Immune Defenses Against Tumor Cells Copyright ©2021 F.A. Davis Company  Body Defenses Against Cancer Copyright ©2018, Elsevier Inc. All rights reserved. 19 Copyright ©2021 F.A. Davis Company  Immunoedi7ng and Tumor Escape Copyright ©2021 F.A. Davis Company  Tumor Evasion of Immune System § An7-tumor an7bodies o Might actually block sites for CTL to bind § Tumor cells might express less Class I MHC o This prevents CTL-mediated death § Tumor cells may provide poor cos7mulatory signals Copyright ©2021 F.A. Davis Company  Tumor Markers § Glycoproteins found in small amounts in normal serum, but elevated in certain types of cancer. § Can be used to o Screen for cancer o Monitor therapeutic response o Determine tumor burden Copyright ©2021 F.A. Davis Company Carcinoembryonic An7gen (CEA) § Used in management of GIT tumors o Colon cancer & adenocarcinoma of the colon o Pancreas, liver, and lung § Found in o Infalmmatory bowel disease (IBD) o Ulcera7ve coli7s, polyps, tumors of GIT, Crohn disease and cigareUe smokers § The highest levels of CEA are found in metasta7c disease Copyright ©2021 F.A. Davis Company  Carcinoembryonic An7gen (Con.) § CEA levels in normal people range up to 2.5 ng/ml. § Levels that are 4-5 7mes normal have been used to predict recurrence of colo-rectal tumors. Copyright ©2021 F.A. Davis Company  α-Fetoprotein (AFP) § High levels in pa7ents with o Hepatocellular carcinoma & hepatoblastoma o Tes7cular & ovarian cancer o Viral hepa77s & cirrhosis o Ulcera7ve coli7s § Very important marker in monitoring cancer therapy Copyright ©2021 F.A. Davis Company  α-Fetoprotein (AFP)/Con. § The normal range of AFP concentra7ons in humans is 0-20 ng/ml. § A 5-fold or higher rise in this protein is used for monitoring hepatomas and tes7cular cancers. § AFP level may also be raised in some non- malignant condiYons, such as cirrhosis, in hepa77s and other forms of liver damage. Copyright ©2021 F.A. Davis Company  Human Chorionic Gonadotropin (HCG) § Composed of 2 subunits: α & β (β-HCG). o Found in serum and urine during pregnancy. § Produced by neoplas7c cells of tes7cular cancer and other tumors. § Levels of (β-HCG) are useful in evalua7ng pa7ents with: Gesta7onal trophoblas7c disease o o Tes7cular tumors o Ovarian germ cell tumor. § Normal range: Adults: < 15 ng/ml in normal men. Copyright ©2021 F.A. Davis Company  Prostate-Specific An7gen (PSA) § Glycoprotein that dissolves seminal gel a[er ejacula7on § Found in very low amount in blood in normal individuals § Increased in: o Prostate cancer. o Benign prosta7c hypertrophy o Acute & chronic prosta77s § Levels correlate with o Prostate size, and stage of cancer o response to treatment § Used to screen for prostate cancer in conjunc7on with digital rectal examina7on § PSA level below 4 ng/mL Copyright ©2021 F.A. Davis Company  Clinically Relevant Tumor Markers § Biological substances found in increased amounts in blood, body fluids, or 7ssues of pa7ents with a specific type of cancer. § Concentra7on in serum depends on amount of tumor cell prolifera7on and tumor size. § Elevated level indicates a significant tumor mass. § Ideally, should be highly sensi7ve and specific. Copyright ©2021 F.A. Davis Company  Clinical Uses of Tumor Markers § Popula7on screening To iden7fy cancer in asymptoma7c people (e.g., PSA) May detect cancer at an early stage but can get false-posi7ve or false-nega7ve results. § Diagnosis Iden7fies cancer in a par7cular pa7ent (e.g., PSA). Copyright ©2021 F.A. Davis Company  Common Serum Tumor Markers Marker Cancer(s) Uses AFP Liver, tes7cular S, D, P, M CA 125 Ovarian S, D, P, M CA 19-9 Pancrea7c D, P, M CEA Colorectal, breast, lung P, M D, P, M hCG Tes7cular, trophoblas7c PSA Prostate S, D, P, M Copyright ©2021 F.A. Davis Company  Laboratory Tests for Tumors § Immunohistochemistry Uses labeled an7bodies to detect tumor an7gens in 7ssue biopsies. § Immunoassays Measure levels of circula7ng tumor markers. § Molecular methods Detect gene7c muta7ons associated with cancer. e.g., PCR, karyotyping, FISH, microarray, DNA sequencing Copyright ©2021 F.A. Davis Company  Immunotherapy § Also known as biological response modifier therapy § Uses ability of the immune system to destroy tumor cells. § Ac7ve immunotherapy S7mulates pa7ent’s immune system to respond to tumor an7gens Cancer vaccines: preventa7ve (HPV, HBV) or therapeu7c (TSA-specific, Provenge) Copyright ©2021 F.A. Davis Company  Passive Immunotherapy § Administra7on of soluble components of the immune system § Cytokines to nonspecifically boost the immune response and increase white blood cell produc7on e.g., GM-CSF, IL-2, IFN-α Copyright ©2021 F.A. Davis Company  Passive Immunotherapy (con7nued) § Monoclonal an7bodies that target specific tumor an7gens: Surface an7gens Receptors Angiogenesis factors Immune checkpoint molecules An7body–drug conjugates (immunotoxins) Bi-specific monoclonal an7bodies Copyright ©2021 F.A. Davis Company  Adop7ve Immunotherapy § Transfer of cells of the immune system § TILs to melanoma pa7ents § Gene7cally engineered T cells (CAR-T) Copyright ©2021 F.A. Davis Company