Immunology BIOT 203 Fall 2023 Past Paper PDF

Important Updates 1. Group Presentation – 20% of final grade o Must be enrolled in a group today for Final Presentation Assignment Today. If you do not you will NOT be able to submit 2. Next week is last lecture!! 3. Case Study on November 29th – 15% of final grade o 4. stay tuned for more...

Important Updates 1. Group Presentation – 20% of final grade o Must be enrolled in a group today for Final Presentation Assignment Today. If you do not you will NOT be able to submit 2. Next week is last lecture!! 3. Case Study on November 29th – 15% of final grade o 4. stay tuned for more details to come. Final Exam – 20% of final grade o o o o o In class – Dec 6, 2023 Cheat sheet allowed and format same as with midterm Cumulative (All units) – 2/3 of questions from Modules 7-10 You will have 1h 40m 50 questions (MC, Matching, T/F) Fall 2023 | J.Memme IMMUNOLOGY | BIOT 203 1 Tumor & Carcinogenic Immunity IMMU N OL OGY | B IOT 203 FA L L 2 0 2 3 | W E E K 1 0 D R . JON AT H A N ME MME Fall 2023 | J.Memme IMMUNOLOGY | BIOT 203 2 Tumor & Carcinogenic Immunity TOPICS LEARNING OBJECTIVES Tumor Antigens Describe tumor-induced protective immune response Immune Response to Tumors Tumor Evasion from Immune System Immunotherapy for Tumors Tumor Growth Promotion Classify and describe tumor antigens Explain methods by which tumors evade immune response Explain the role of immunotherapy for tumors Discuss the role of innate and adaptive immunity in tumor growth promotion Fall 2023 | J.Memme IMMUNOLOGY | BIOT 203 3 Tumor Immunity Tumor Oncogenic Carcinogenic Oncogenes Oncology Fall 2023 | J.Memme • Abnormal growth of cells with no purpose or function • Benign tumor: does not invade surrounding tissues or spread to other areas of the body • Malignant tumor: does invade or spread; Cancer • Causes tumor development • Causes cancer development • Genes that have the potential to become dominant oncogenic determinants in tumorigenesis • Mutated and/or expressed at high levels in tumor cells • Medical field focused on the prevention, diagnoses, and treatment of tumors and cancer • Practicing doctor: Oncologist IMMUNOLOGY | BIOT 203 4 Tumor Immunity A Resect tumor surgically cured Experimental demonstration: Tumors can induce protective immune response Tumors express antigens, but are weakly immunogenic ◦ Derived from host cells and promote immune response ◦ T-cell mediated defense B A Immune response often fails to prevent the growth of tumors B ◦ Derived from host cell (self) ◦ Rapid growth exceeds immune system capacity ◦ Tumors are specialized to evade immune response Immune system can be stimulated to kill tumors ◦ Tumor immunotherapy A No tumor growth rejected B B Tumor growth Tumor eradicated rejected accepted Image credit: Abbas, Lichtman, & Pillai, 2007, p. 398 Fall 2023 | J.Memme IMMUNOLOGY | BIOT 203 5 Tumor Immunity Red arrow: malignant cells Yellow arrow: Lymphocyte-rich inflammatory infiltrate (T-c cells and macrophages) Fall 2023 | J.Memme IMMUNOLOGY | BIOT 203 6 Tumour Immunology and Immunotherapy https://youtu.be/K09xzIQ8zsg?si=7dFAIhlX7LStVKHz Fall 2023 | J.Memme IMMUNOLOGY | BIOT 203 7 Recall: Tumor Antigens Mutated Genes (neoantigens) Tumor-restricted antigens ◦ Expressed on tumor cells BUT NOT normal cells ◦ Unique to individual tumors ◦ Shared among tumors of the same type Oncogenic Virus Antigens Abnormally Expressed Proteins Oncofetal Antigens Modified Glycolipid & Glycoprotein Antigens Tumor-associated antigens ◦ Expressed on tumor cells AND normal cells ◦ Normal cell components with dysregulated expression Tissue-Specific Differentiation Antigens *Potential application as therapeutic TARGETS!* Image credit: Abbas, Lichtman, & Pillai, 2007, p. 402 Fall 2023 | J.Memme IMMUNOLOGY | BIOT 203 8 https://www.youtube.com/watch?v=AN8FMwDg0jM RAS BRAF MEK ERK Mutated Genes Oncogenic mutation of normal genes Randomly mutated genes Gene expression that promotes malignant transformation Tumors induced by the same carcinogen (Chemical carcinogen, radiation) can express different antigens ◦ Causes: Point mutation, deletions, chromosomal translocations, viral gene insertion Ras mutations ◦ Ras proteins can be switched on by incoming signals, which turn on other proteins that activate genes involved in cell growth, survival and differentiation ◦ Mutations in Ras genes can permanently activate Ras proteins Protein synthesis ◦ An induced sarcoma promotes protective immunity against itself, but NOT against another induced sarcoma ◦ Diverse antigens arise because tumors randomly mutate the host genes Antigen presentation Oncogenic/mutated self-proteins are synthesized and are presented via MHC class I Image credit: Abbas, Lichtman, & Pillai, 2007, p. 402 Fall 2023 | J.Memme IMMUNOLOGY | BIOT 203 9 Oncogenic Virus Antigens Oncogenic virus functions as tumor antigen, promoting T cell response Viral microbe integrates genomic sequence into host DNA or RNA Adaptive immunity prevents the growth of DNA virus-induced tumors The most immunogenic tumors ◦ Viral peptide antigens replicate!! ◦ Antigen processed and displayed via MHC Class I DNA virus-induced tumors ◦ Higher frequency of EBV lymphomas and HPV cervical cancer reported for immunosuppressed individuals ◦ Protective VIRAL immunity may be achieved via immunization … reducing the risk of developing the related cancer ◦ HPV vaccine ◦ Epstein-Barr virus → lymphomas ◦ Human papillomavirus → cervical cancer Image credit: Abbas, Lichtman, & Pillai, 2007, p. 402 Fall 2023 | J.Memme IMMUNOLOGY | BIOT 203 10 Abnormally Expressed Proteins Normal cellular proteins with abnormal expression in tumor cells that promote immune response Explanation Tyrosinase Vaccine potential ◦ Enzyme involved in melanin biosynthesis ◦ Tc and Th cells from melanoma patients recognize peptides derived from tyrosinase ◦ Recognize normal self antigen! ◦ Enzyme is produced in small quantities and in a small number of cells ◦ Not recognized by immune system ◦ Tyrosine-restricted T cell response in melanoma patients ◦ Vaccine has potential to stimulate response to melanomas Image credit: Abbas, Lichtman, & Pillai, 2007, p. 402 Fall 2023 | J.Memme IMMUNOLOGY | BIOT 203 11 Oncofetal Antigens Proteins normally expressed in developing fetal tissue, but not expressed in adult tissue and Overexpressed in cancer cells ◦ Oncofetal antibody is the product of Carcinoembryonic antigen (CEA) ◦ Highly glycosylated membrane protein, member of Ig superfamily ◦ Normal fetus: first two month of development concentrated in gut, pancreas, liver ◦ Normal adult: low expression in colonic mucosa and lactating breast Oncofetal genes ◦ Carcinoma of liver, pancreas, stomach, breast Antigens also related to various inflammatory conditions α-fetoprotein (AFP) Diagnosis: Serum concentrations of oncofetal antigens ◦ Indicators of advancement ◦ Persistence or recurrence after treatment Fall 2023 | J.Memme ◦ Circulating glycoprotein synthesis and secreted during fetal development ◦ Hepatocellular carcinoma, germ cell tumor, gastric, pancreatic cancer IMMUNOLOGY | BIOT 203 12 Modified Glycolipid & Glycoprotein Antigens Elevated levels or abnormal expression of surface glycolipid and glycoproteins Melanoma ◦ Overexpressed glycolipids (GM2, GD2, GD3) ◦ Antibody and immunization clinical trials ◦ Cell surface properties are altered Breast Ductal carcinomas HYPERglycosylated HYPOglycosylated ◦ MCU-1: membrane bound protein normally expressed in breast ductal tissues ◦ Hyperglycosylated MCU-1 ◦ Ductal carcinomas, MCU-1 contains tumorrestricted carbohydrate and peptide epitopes ◦ T cell and antibody response Adapted from: https://www.researchgate.net/profile/Marc_Gregoire/publication/236062195/figure/fig1/AS:319913689403392@1453284775543/Structure-of-the-MUC1-glycoprotein-in-normal-and-tumor-cells.png Fall 2023 | J.Memme IMMUNOLOGY | BIOT 203 MCU: Mitochondrial Calcium Uniporter Allows passage of Ca2+ into mitochondria 13 Tissue-Specific Differentiation Antigens Antigen found on the surface of the cell, specific to cell tissue. TSDA become abnormal on surface of tumor. Differentiation antigens ◦ Surface antigens that are normally expressed on the cells from which the tumor has originated ◦ Glycolipid and glycoprotein which may have abnormal structure, caused by tumor growth TSDA can be used as Tumor Markers: Biomarkers which become elevated in the presence of tumors. Immunoassay used to determine the presence of Tumor by measuring level of tumor markers. Immunotherapy used to treat tumor. Fall 2023 | J.Memme IMMUNOLOGY | BIOT 203 14 Immune Response to Tumors Innate and adaptive immunity are shown to effectively kill tumor cells in vitro Mechanisms that contribute to protective immunity in vivo Enhance effector mechanisms to be tumor specific However, effector mechanisms to PROTECT from tumors is NOT well defined Explore evidence for various immunity effector mechanisms that may be applicable to human tumors Innate and adaptive immune system Fall 2023 | J.Memme IMMUNOLOGY | BIOT 203 15 Innate Immune Response | NK Cells NK cells respond to the absence of MHC I molecules ◦ Tumor cells may lose MHC I expression NK cell target IgG coated cells ◦ NK Fc receptor interacts with antibody bound to tumor antigen ◦ Cytokines released ◦ Apoptosis of tumor cell Enhanced NK Cell activity by cytokines ◦ IL-2 activated NK cells = Lymphokine activated killer ◦ Applications in immunotherapy By Simon Caulton - Own work, CC BY-SA 3.0, https://commons.wikimedia.org/w/index.php?curid=29704984 Fall 2023 | J.Memme IMMUNOLOGY | BIOT 203 16 TNF signals through two transmembrane receptors (TNFR1 and TNFR2) and regulates several critical cell functions in a healthy system. Innate Immune Response | Macrophage Tumor necrosis factor | TNF Activated macrophages show ability to kill tumor cells with greater efficiency, compared to when killing normal cells. ◦ Cytokine released by macrophages that induces apoptosis in tumor cells ◦ Tumor cells have a receptor for TNF It is unknown exactly how tumor cells activate macrophages ◦ Direct recognition OR activation by interferon gama (INF-γ) ◦ In vitro studies of INF-γ shown to inhibit tumor growth and proliferation Killing mechanism ◦ Enzymes, reactive oxygen species, nitric acid By Fred the OysteriThe source code of this SVG is valid.This vector graphics image was created with Adobe Illustrator., GFDL, https://commons.wikimedia.org/w/index.php?curid=36260143 Fall 2023 | J.Memme IMMUNOLOGY | BIOT 203 17 Video: https://www.youtube.com/watch?v=OPEdEU9FImg Adaptive Immune Response | Tc Cells Tc provide effective anti-tumor immunity in vivo ◦ Recognize and kill cells that express peptides from mutant cellular proteins, oncogenic viral proteins Tc response for tumor antigens may require cross-presentation of antigen by APCs ◦ Co-receptor and MHC I Image credit: Abbas, Lichtman, & Pillai, 2007, p. 408 Fall 2023 | J.Memme IMMUNOLOGY | BIOT 203 18 Adaptive Immune Response | Th Cells Role of Th is less understood Release cytokines (TNF and IFN-γ) ◦ Enhance Tc development and specificity ◦ Promote MHC class I expression on tumor cells, making them more attractive to Tc ◦ Activate macrophages ◦ Cytokine profile ◦ Chemokines, Interferons, Interleukins, Lymphokines, Tumor Necrosis Factor Image credit: Abbas, Lichtman, & Pillai, 2007, p. 408 Fall 2023 | J.Memme IMMUNOLOGY | BIOT 203 19 Adaptive Immune Response | Antibodies Antibodies may be produced against tumor antigens ◦ Epstein-Barr virus (EBV)-antigens on lymphoma cells ◦ There is no effective vaccine available yet to treat this virus Antibody-dependent cell-mediated cytotoxicity Little evidence for effective humoral immunity Antibody response, B cells are activated to secrete immunoglobulins Potential for prevention ◦ Fc receptor macrophage or NK cell ◦ Circulate in the bloodstream, binding to the foreign antigen/virus Fall 2023 | J.Memme ◦ Vaccination against oncogenic viruses ◦ EBV vaccine trials have been conducted for Phase I virus using a modified version of modified vaccinia Ankara vaccine IMMUNOLOGY | BIOT 203 20 Evasion of Immune Response of Tumors Anti-tumor immunity Tumor immune evasion • Tumor antigens promote T-cell response and antibody production • Tumor antigens are not expressed • Mutation or downregulate expression of MHC molecules • Immunosuppressive substances are produced • Induce tolerance to tumor antigens • tumor cells can be killed by Tc, NK, macrophage Understand how tumor cells EVADE immune destruction à design interventions to increase immunogenicity of tumors Fall 2023 | J.Memme IMMUNOLOGY | BIOT 203 21 VIDEO: Cancer: Evading the Immune System https://www.youtube.com/watch?v=ovaUf53LPMA Evasion Specific immunological tolerance is induced by tumor antigens ◦ Tumor antigens may be self-antigens T cell response is supressed by regulatory T cells Expression of tumor antigens is downregulated or lost Tumor cells not expressing MHC class I do not induce Tc cells Tumor cells produce products that suppress anti-tumor response, inhibiting T cell activation Image credit: Abbas, Lichtman, & Pillai, 2007, p. 408 Fall 2023 | J.Memme IMMUNOLOGY | BIOT 203 22 Tumor Growth Promotion Chronic inflammation and infection ◦ Risk factor for cancer development ◦ Cancer is an indirect result of carcinogenic effects of chronic inflammatory states Gastric cancer related to chronic H. pylori infection Liver cancer (HCC) related to Heb B and Hep C viral infections Fall 2023 | J.Memme IMMUNOLOGY | BIOT 203 Inflammation • Tissue damage or infection • Cells divide, grow, repair/rebuild tissue • Inflammation ends à healthy tissue Chronic inflammation • Inflammation does not end • Reoccurring infections, autoimmune response, obesity • DNA damage à cancer 23 Tumor Growth Promotion | Adaptive Immunity Promote chronic activation of innate cells ◦ T-cell mediated activation of macrophage (persistent intercellular microbial infection) Enhance tumor-promoting actions of innate immunity Activation of Treg cells by tumors can suppress anti-tumor immunity of Tc and Th cells. Jen, J., Lin, L.-L., Chen, H.-T., Liao, S.-Y., Lo, F.-Y., Tang, Y.-A., … Wang, Y.-C. (2015). Oncoprotein ZNF322A transcriptionally deregulates alpha-adducin, cyclin D1 and p53 to promote tumor growth and metastasis in lung cancer. Oncogene, 35(18), 235 Fall 2023 | J.Memme IMMUNOLOGY | BIOT 203 24 Tumor Growth Promotion | Innate Immunity Chronic activation of macrophages ◦ Most direct tumor-promoting culprits of all immune cells ◦ Characterized by the formation of new blood vessels and tissue remodelling Malignant transformation of cells ◦ Generation of DNA-damaging free radicles ◦ Mutations in tumor-supressing genes Recall that electrons like to be paired Free radicals: atoms with unpaired electrons ◦ Electron is ‘stolen’ when interacting with oxygen ◦ Initiate CHAIN REACTION Antioxidants: donate electron to free radicles Chemical massagers released by mast cell, neutrophils, macrophages ◦ Encourage cell cycle progression ◦ Promote survival of tumor cells https://www.h2miraclewater.com/wp-content/uploads/2015/03/free-radical.png Fall 2023 | J.Memme IMMUNOLOGY | BIOT 203 25 Tumor Growth Promotion | Innate Immunity Chronic activation of macrophages ◦ Most direct tumor-promoting culprits of all immune cells ◦ Characterized by the formation of new blood vessels and tissue remodelling Malignant transformation of cells ◦ Generation of DNA-damaging free radicles ◦ Mutations in tumor-supressing genes Recall that electrons like to be paired Free radicals: atoms with unpaired electrons ◦ Electron is ‘stolen’ when interacting with oxygen ◦ Initiate CHAIN REACTION Antioxidants: donate electron to free radicles Chemical massagers released by mast cell, neutrophils, macrophages ◦ Encourage cell cycle progression ◦ Promote survival of tumor cells https://www.h2miraclewater.com/wp-content/uploads/2015/03/free-radical.png Fall 2023 | J.Memme IMMUNOLOGY | BIOT 203 26 Tumor Growth Promotion | A Paradox Protective anti-tumor adaptive immune response Paradox Challenge Opportunity Intervention Beneficial balance Control chronic inflammatory conditions Anti-tumor adaptive immune response is not compromised Control of chromic inflammatory conditions Fall 2023 | J.Memme IMMUNOLOGY | BIOT 203 27 Goal: Promote active immune response against tumor cells https://www.youtube.com/watch?v=K09xzIQ8zsg Immunotherapy for Tumors Tumor-specific immune effector •Highly specialized and individualized Active enhancement of immune response •Vaccination with tumor cells and/or antigens •Administer tumors modified to express elevated levels of costimulators, stimulating T cell response •Systemic administration of cytokines Immune Checkpoint blockade therapy Adoptive T-cell immunotherapy (CAR T-cell therapy) Passive immunotherapy Fall 2023 | J.Memme •Block inhibition pathways •Block CTLA-4, PD-1 •Patient’s immune cells are removed and modified, re-injected •Intensifies natural immune response •Anti-tumor antibodies •Antibodies-drug conjugate (immunotoxins) •Tumor-reactive T cells and NK cells that have been isolated and proliferated in vitro IMMUNOLOGY | BIOT 203 28 Tumor Vaccines Tumor-antigen pulsed dendritic cells ◦ Dendritic cell incubated with tumorantigen peptide ◦ APC expressing MHC/antigen is target for Tc cells ◦ Tumor-specific Tc cells are activated DNA or transfected dendritic cell ◦ Transfect: introduced ‘naked’ nucleic acid into cells ◦ Direct or indirect ◦ APC expressing MHC/antigen is target for Tc cells ◦ Tumor-specific Tc cells are activated Image credit: Abbas, Lichtman, & Pillai, 2007, p. 411 Fall 2023 | J.Memme IMMUNOLOGY | BIOT 203 29 Exercise and Cancer Prevention - decreased incidence of metabolic syndrome (second to smoking in cancer risk) - reduced basal insulin levels, improved glucose handling and digestion - increased metabolic maintenance in the body (mitochondrial content, especially muscle) - improved regulation of growth factors that can be tumorigenic - Reduced systemic inflammation and improved immune function è Fall 2023 | J.Memme IMMUNOLOGY | BIOT 203 30 Progress Tracking Assessment #9 Available on Blackboard in Unit Learning Materials ◦ You are in encouraged to collaborate with your peers but must submit your own individual product. ◦ Submit via Blackboard using the assignment submission link before the end of the day By Simon Caulton - Own work, CC BY-SA 3.0, https://commons.wikimedia.org/w/index.php?curid=29704984 IMMUNOLOGY | BIOT 203 Fall 2023 | J.Memme 31