Final Exam Practice PDF - Immune Regulation and Vaccination

Final Exam Practice https://www.classroomclipboard.com/506207/Test/38E7A3A3-3DCA-439C-BC54- 2960D034C5A4 Code: JCGH64P 10 questions, 10 minutes! Topic: Immune regulation and Vaccination Write your name: DO: Nguyen Thi Thu Hoai DON’T: Nguyễn Thị Thu Hoài...

Final Exam Practice https://www.classroomclipboard.com/506207/Test/38E7A3A3-3DCA-439C-BC54- 2960D034C5A4 Code: JCGH64P 10 questions, 10 minutes! Topic: Immune regulation and Vaccination Write your name: DO: Nguyen Thi Thu Hoai DON’T: Nguyễn Thị Thu Hoài NTTH-HCMIU-IM  Immunity in Defense and Disease Apply what you have learnt to understand - Immunological defenses against Microbes - Immunological defenses against Tumors - Reaction against Transplant - Diseases caused by abnormal immune response NTTH-HCMIU-IM  IMMUNOLOGICAL DEFENSES AGAINST TUMORS Table of content: I. Introduction to Cancer: Tumor vs. Cancer; II. Immune response against tumor: Tumor Immunity/ Immuno- Oncology 1. Tumor antigens 2. Immune response to tumor 3. Evasion of immune responses by tumor 4. Immunotherapy for cancer 5. Role of immune system in promoting tumor growth NTTH-HCMIU-IM  I. Introduction to Cancer Tumor- Cancer An abnormal new growth of tissue that grows more rapidly than normal cells and will continue to grow if not treated. These growths Neoplasm will compete with normal cells for nutrients. This is a non-specific term that can refer to benign or malignant growths. A synonym for tumor. The more commonly used term for a neoplasm. The word tumor Tumor simply refers to a mass. This is a general term that can refer to benign or malignant growths. A non-malignant/non-cancerous tumor. A benign tumor is usually Benign localized, rarely spreads to other parts of the body and responds well tumor to treatment. However, if left untreated, benign tumors can lead to serious disease. Malignant Cancer. A malignant tumor is resistant to treatment, may spread to tumor other parts of the body (metastasis) and often recurs after removal. Cancer A malignant tumor (a malignant neoplasm). http://pathology.jhu.edu/pc/BasicTypes1.php NTTH-HCMIU-IM  Metastasis Spreading of cancerous cells via blood or lymph to various tissues 22.1 NTTH-HCMIU-IM  Types of Cancers 1. Carcinoma: endodermal/ ectodermal tissue 2. Sarcoma: mesodermal connective tissues 3. Leukemia/ Lymphoma: Hematopoietic stem cells- Cancer of the IS NTTH-HCMIU-IM A blink on Developmental Biology NTTH-HCMIU-IM  Tumors of the Immune System Lymphomas – Solid tumors w/in lymphoid tissue (bone marrow, lymph nodes, thymus) – Hodgkin’s & non-Hodgkin’s (Presence/ Absence of Reed-Sternberg cells) http://www.lymphomainfo.net/ Leukemias – Proliferate as single cells – Acute or Chronic depending on the progression of disease Acute- appear suddenly and progress rapidly; arise is less mature cells (ie ALL, AML) Chronic- much less aggressive and develop slowly; mature cells (ie CLL and CML) What is Lymphoma? - YouTube NTTH-HCMIU-IM  What makes cancer “cancer”? 1. decreased requirements for growth factors (EGF, estrogen, Ils, etc.) and serum (cytokines, etc?). 2. are no longer anchorage dependent. 3. grow independently of density. Normal cells: eventually enter Go CHECKPOINT FAILURE contact inhibition NTTH-HCMIU-IM  Malignant Transformation Two phases: 1. initiation (changes in genome) – chemical and physical carcinogens/ mutagens – virally induced transformation: oncogene: “cancer gene”; often found in viral genomes – Activation/ Problem of proto-oncogene (p53): cellular counterpart which can be turned into an oncogene 2. promotion (proliferation) NTTH-HCMIU-IM  II. Immune responses against tumor: Tumor immunity Tumour cells differ from normal cells => recognition as foreign HOW ARE THEY DIFFERENT TO NORMAL ONES? SIGNS OF ROLE OF IMMUNE SYSTEM IN DEFENDING TUMOR ✓Spontaneous regression; ✓ Regression of metastases after removal of the primary tumour; ✓ Infiltrations of tumours by lymphocytes and macrophages; ✓ Lymphocyte proliferation in draining lymph nodes; ✓ Increased cancer risk after immunosuppression and immunodeficiency NTTH-HCMIU-IM  II. Immune responses against tumor: Let‘s look into them 1. Tumor antigens 2. Immune response 3. Evasion of immune responses 4. Role of immune system in promoting tumour growth 5. Cancer treatment therapies: immunotherapy NTTH-HCMIU-IM  1. Tumor antigens TAs: the new antigen produced by tumor cells; specific for tumor cells; cause cell immune response and humoral immune response. TSTAs: Tumor Specific Transplantation Antigen: Unique to tumor cells DO NOT occur on normal cells in the body ✓ Novel proteins created by mutation presented on class I MHC; ✓ Can either be chemically/physically induced or virally induced tumor antigens. TATAs: Tumor Associated Transplantation Antigen NOT unique to tumor cells DO occur on normal cells in the body So where’s the problem with TATAs? ✓Fetal/adult presence; ✓Concentration of Growth Factors and Growth Factor Receptors; ✓Oncofetal Tumor Antigens (AFP & CEA); ✓Normally appear in fetus before immunocompetence; ✓Later recognized as non-self. NTTH-HCMIU-IM  1. Tumor antigens TAs may be of... a. Abnormal expression: oncofetal antigens, altered surface modifications, tissue specific differentiation antigens, oncogenic viruses. b. Mutations: point-mutations; deletions; translocations; insertions NTTH-HCMIU-IM a. Abnormal Expression NTTH-HCMIU-IM b. Mutation NTTH-HCMIU-IM  Chemically/Physically Induced cancer Specific Immunologic Response that can protect against later challenge by live cells; Of the same line but not other tumor-line cells. Methylcholanthrene / UV light. NTTH-HCMIU-IM  Virally Induced cancer Express tumor antigens shared by all tumors induced by the same virus Burkitt’s Lymphoma – Epstein Barr Cervical cancer - HPV (E6, E7) NTTH-HCMIU-IM Origin of tumor antigens NTTH-HCMIU-IM NTTH-HCMIU-IM Example of one famous oncogene: Tumor Suppressor p53- the guardian of the genome The Role of p53 in Cancer - YouTube NEOPLASIA 4: p53 gene: The Guardian of the genome. functions, regulation and inactivation - YouTube The gene TP53, discovered in 1979 http://en.wikipedia.org/wiki/P53 NTTH-HCMIU-IM  Example of one famous mutation: BCR/ABL The Philadelphia chromosome or Philadelphia translocation is a specific abnormality of chromosomal chromosome 22, which is unusually short, as an acquired abnormality that is most commonly associated with chronic myelogenous leukemia (CML) The Translocation gives rise to a fusion gene, bcr-abl, that juxtaposes the Abl1gene on chromosome 9 (region q34) to a part of the BCR ("breakpoint cluster region") gene on chromosome 22(region q11). http://en.wikipedia.org/wiki/Philadelphia_chromosome NTTH-HCMIU-IM BREAST CANCER ASSOCIATED GENES A guide to BRCA1 and BRCA2 gene mutations in hereditary breast and ovarian cancer - YouTube NTTH-HCMIU-IM  II. Immune reactions against tumor: Let‘s look into them 1. Tumour antigens 2. Immune response 3. Evasion of immune responses 4. Role of immune system in promoting tumor growth 5. Cancer treatment therapies: immunotherapy NTTH-HCMIU-IM  2. Immune responses to tumors Innate immune responses NK cells macrophages CMI Adaptive immune responses T cells Antibodies HI NTTH-HCMIU-IM  So, you have a tumor cell. Now what? Development of Adaptive immune response against cancer 1. Seeing the cancer (Cancer surveillance) Ternary complex (MHC-Ag-TCR) and co-stimulation by B7 2. Activating lymphocytes Release IL-2, IFN-gamma, and TNF-alpha 3. Patrolling and Killing CMI: CTL lysis, macrophages, NK cells Humoral IR NTTH-HCMIU-IM Evidence of CTL roles in tumor defense StudentConsult NTTH-HCMIU-IM  Role of CTLs in tumor treatment StudentConsult NTTH-HCMIU-IM NTTH-HCMIU-IM  CMI: CTL lysis, macrophages, NK cells B7 CD28 Kill directly CTL Kill directly apoptosis NK apoptosis MHC ADCC TCR CK effect Fas CK effect Fas L Tumor antigen MHC B7 CD28 TCR Th Th MΦ MHC TCR Cytokines CD28 B7 (CK) Cytokines (CK) ADCC MΦ Kill directly Ag presentation Apoptosis indirectly NTTH-HCMIU-IM Others: DC γδ T cell B-1 cell Neutrophil NTTH-HCMIU-IM  Humoral IR 1. Complement-fixing Abs → bind to the tumor cell membrane and promote attachment; create pores in the membrane → cell disruption due to the loss of osmotic and biochemical integrity. 2. Opsonization of Ab to Ag 3. Immune complex 4. Interference of tumor cell adhesion NTTH-HCMIU-IM But if the body has all these defenses, why do so many people still have cancer? NTTH-HCMIU-IM  3. Evasion of IR Mechanisms by which tumors escape immune recognition: 1. Interfering with antigen presentation: Low immunogenicity, Tumor treated as self antigens, Antigenic modulation; 2. Generating tumor induced privileged site 3. Suppressing immune system: Tumor induced suppression NTTH-HCMIU-IM Interfering with antigen presentation : Regulation and absence of MHC Diminution of MHC-I molecules s α2 s α1 s s α3 s β2m s Absence of β2m gene cause the absence of peptide/heavy chain/ β2m complex NTTH-HCMIU-IM  Switch to other HLA-1 types Some non-classical MHC express upward Such as HLA-E ,HLA-G molecules CD49/ NKG2A- HLA-E inhibitory receptor Transduct inhibitory signals KIR- HLA-G killing inhibitory receptor Inhibit the activity of NK cell and CTL NTTH-HCMIU-IM 3.1. Interfering with antigen presentation Covering or blocking of tumor antigens on the surface of the tumor cells Low immunogenicity of tumor antigens and antigenic modulation T cell Tumor cell NTTH-HCMIU-IM Lack of Co- Stimulatory Signal Abnormal express of other molecules on the surface of the tumor cells Lack of co-stimulatory molecules Changes of express level of important adhesion molecules Block the transduction of apoptosis signals → Induce the irresponsibility of tumor infiltration lymphocyte: Induce T cell apoptosis Induce T cell anergy NTTH-HCMIU-IM 3.3. Tumor induced immune suppression: Secrete soluble immune inhibitors: TGF-b, IL-10 Immune stimulation: IL-4, IL-10 NTTH-HCMIU-IM  TGF-beta IL-10 VEGF Effect Inhibition of T-cell growth + - + Inhibition of CTL differentiation + + + Inhibition of cytokine production + + - Induction of T-cell anergy + - - Downregulation of cytotoxic potential + + - Inhibition of antigen presentation + + - Shift in the Th1-Th2 balance towards Th2 + + - Downregulation of adhesion/costimulatory molecules + + - Resistance to CTL-mediated lysis - + - Source: Chouaib et al 1997 NTTH-HCMIU-IM 3.3 Tumor- induced privileged sites Collagen, etc. NTTH-HCMIU-IM  II. Immune reactions against tumor: Let‘s look into them 1. Tumor antigens 2. Immune response 3. Evasion of immune responses 4. Role of immune system in promoting tumor growth 5. Cancer treatment therapies: immunotherapy NTTH-HCMIU-IM 4. Role of IS in promoting tumor growth Bad antibodies? Some antibodies do not protect against tumor growth but ENHANCE it. Release of immunosuppressive cytokines transforming growth factor-beta (TGF-beta), interleukin-10 (IL-10) and vascular endothelial growth factor (VEGF) Chronic inflammation as risk factor for cancer Helicobacter pylori (gastric cancer) Hepatitis B and C (hepatocellular carcinoma) NTTH-HCMIU-IM Immunotherapy: How the Immune System Fights Cancer - YouTube YEAH, Sometimes IRs fail to prevent tumor growth →Requires help from outside WHAT SHOULD IT BE? Tumour immunology and immunotherapy (youtube.com) NTTH-HCMIU-IM 5. Cancer treatment therapi A. Operation B. Radiacal therapy C. Chemical therapy D. Biological therapy D. → Immunotherapy NTTH-HCMIU-IM  D. Immunotherapy D.1 Passive immunotherapy Antibodies (mAb) Adoptive cellular therapy D.2 Active immune therapy: Stimulation of immune response Vaccination with tumor cells- Cancer vaccine Costimulators and cytokines Enhancement of APC activity Block inhibitory pathways Non-specific stimulation of the immune system NTTH-HCMIU-IM D.1 Passive Immunotherapy D1.1Monoclonal antibodies How Monoclonal Antibodies Treat Cancer #cancer #monoclonala ntibodies (youtube.com) NTTH-HCMIU-IM  D.1 Passive Immunotherapy FDA approved therapeutic monoclonal antibodies Tumor specific Abs ImmunoToxins Inhibtion of PD-1 https://www.youtube.com/watch?v=aQxbKHSzLyU NTTH-HCMIU-IM Procedure of immunotherapy/ Production of mAbs NTTH-HCMIU-IM  D.1 Passive Immunotherapy D1.2 Adoptive T-cell therapy ✓the cells transferred capable of persisting in the host to be effective ✓be treated by the transfer of tumor– specific syngeneic T cell ✓require an extended period There is now substantial experience with adoptive T-cell transfer in humans… NTTH-HCMIU-IM  Gene editing saves girl dying from leukaemia in world first For the first time ever, a person’s life has been saved by gene editing. Layla was diagnosed with acute lymphoblastic leukaemia when she was just three months old. In older children, the treatment, chemotherapy followed by a bone marrow transplant to restore the immune system, is usually successful. November 5th, 2015 Layla was one of the unlucky ones. Cancerous cells were still detectable after the chemotherapy. Despite this, it was decided to go ahead with a bone marrow transplant in order to have graft-versus-leukaemia reaction- but this failed too. The basic idea is to remove immune cells from a patient’s body, genetically engineer them to attack cancerous cells and place them back in the body. Several human trials are already underway around world. Some trials involve adding a gene for a receptor called CAR19, which sits on the outside of the T-cells. This programs the T-cells to seek out and kill any cells with a protein called CD19 on their surface – which is found on the cells that cause acute lymphoblastic leukaemia. Chimeric Antigen Receptor (CAR) NTTH-HCMIU-IM  Layla story- continued But engineering bespoke T-cells for every cancer patient is not cheap. And in Layla’s case, it would not have worked because she didn’t have enough T-cells left to modify. Qasim’s team, however, has been developing “off-the-shelf” treatments, in which T-cells from a healthy donor are modified so they could potentially be given to hundreds of patients. Normally if T-cells from another person were injected into a recipient who was not a perfect match, they would recognise all of the recipient’s cells as foreign and attack them. To prevent this, Qasim’s team used gene editing to disable a gene in the donor cells that makes a receptor that recognises other cells as foreign. The molecular scissors used to disable genes do sometimes make cuts in the wrong place, which carries a small risk of causing adverse effects such as turning cells cancerous. NTTH-HCMIU-IM NTTH-HCMIU-IM  CART, 2017 2015, At the time that Qasim was contacted by Layla’s doctors, his engineered T-cells, called UCART19 cells and developed in collaboration with New York biotech company Cellectis, had only ever been tested in mice. After three months, Layla was given a second bone marrow transplant to restore her immune system. These healthy immune cells recognised the UCART19 cells as foreign and destroyed them, so Layla no longer has any genetically modified cells in her body. After nearly 5 years: 2019, Layla still survive, no return of leukemia! https://www.newscientist.com/article/2119252-gene-editing-has-saved-the- lives-of-two-children-with-leukaemia/ http://labiotech.eu/ucart19-universal-car-t-given-to-another-baby-gosh- cellectis-leukemia/ CAR T-Cell Therapy: Layla’s story – TJNS (wordpress.com) NTTH-HCMIU-IM  CAR-T cells How CAR-T cells work https://www.youtube.com/watch?v=TzSurHZjoy0 FDA Approves First Gene Therapy To Successfully Treat Cancer, 2017 NBC NEWS https://www.youtube.com/watch?v=pZqwbVHEbkY 4 years ago https://www.youtube.com/watch?v=pTQuZ2hWa-0&t=38s NTTH-HCMIU-IM  D.2 Active Immunotherapy Tumor vaccines Reactivation of the immune system: externally and internally NTTH-HCMIU-IM  Immunization to tumor antigen Loading DC with tumor antigens: by a variety of means including transfection, infection with recombinant viruses, incubation with the tumor protein or peptide, or phagocytosis of apoptotic tumor cells Loaded DC can be inoculated into the patient How mRNA cancer vaccines work (youtube.com) to induce responses. NTTH-HCMIU-IM NTTH-HCMIU-IM Costimulation- using costimulators NTTH-HCMIU-IM Costimulation- using costimulators Enhancement of APC activity NTTH-HCMIU-IM  Costimulation- using Cytokine gene transfection Use of recombinant cytokines (singly or in combination) to augment an immune response against cancer via isolation and cloning of various cytokine genes such as: IFN-α, β, and γ; IL-1, 2, 4, 5, and 12; GM-CSF and TNF NTTH-HCMIU-IM Systemic cytokine therapy NTTH-HCMIU-IM  Cytokine Therapy I. Interferons -Most clinical trials involve IFN-α; -Has been shown to induce tumor regression in hematologic malignancies i.e. leukemias, lymphomas, melanomas and breast cancer -All types of IFN increase MHC-I expression -IFN-γ has also been shown to increase MHC-II expression on macrophages and increase activity of Tc cells, macrophages, and NKs II.Tumor Necrosis Factors - Kills some tumor cells; Reduces proliferation of tumor cells without affecting normal cells How?: Hemorrhagic necrosis and regression, inhibits tumor induced vascularization (angio-genesis) by damaging vascular endothelium NTTH-HCMIU-IM A.Lymphocytes are activated against tumor antigens in vitro; Cultured with x-irradiated tumor cells in presence of IL-2; Generated lymphokine activated killer cells (LAKs), which kill tumor cells without affecting normal cells B. Tumors contain lymphocytes that have infiltrated tumor and act in anti-tumor response via biopsy, obtained cells and expanded population in vitro with generated tumor-infiltrating lymphocytes (TILs) NTTH-HCMIU-IM Administration of Monoclonal Antibodies NTTH-HCMIU-IM  SUMMARY: Immune response against tumors Table of content: I. Introduction to Cancer: Tumor vs. Cancer; II. Immune reaction against tumor: Tumor Immunity 1. Tumor antigens: are recognized by immune system 2. Immune response: CTL, NK cells and macrophages 3. Evasion of immune responses 4. Role of immune system in promoting tumor growth 5. Immunotherapy: aims at activating the patient’s own immune system to fight the tumor; Ab therapy NTTH-HCMIU-IM FYI NTTH-HCMIU-IM NTTH-HCMIU-IM From Normal to Abnormal: NTTH-HCMIU-IM  Cancer control Suppressing tumor growth: induction of cellular proliferation inhibition of cellular proliferation, a.k.a. tumor-suppressor genes regulation of programmed cell death Inducing tumor growth chromosomal translocations tandem repeats: HSRs mutations in proto-oncogenes viral integration growth factors and their receptors NTTH-HCMIU-IM Induction of Cancer NTTH-HCMIU-IM NTTH-HCMIU-IM The induction of p53 in response to DNA strand breaks is mediated by the ataxia– telangiectasia mutated (ATM) and ataxia–telangiectasia and Rad3-related (ATR) protein kinases. The role of p53 is to monitor DNA. If damage is detected, p53 triggers repair mechanisms. If repairs are unsuccessful, p53 signals apoptosis NTTH-HCMIU-IM NTTH-HCMIU-IM  Graft-versus leukemia The graft-versus-leukemia effect was initially considered to be a minor component of the graft-versus-host reaction. Clinical bone marrow transplants and Successful treatment of relapsed leukemia with donor lymphocyte transfusions indicate that the graft-versus-leukemia effect can be very powerful and to some degree independent of graft-versus-host disease. Although leukemia cells undoubtedly share common antigens with other tissues of the recipient resulting in nonspecific graft-versus-host and graft-versus-leukemia reactions, there is also the possibility that distinct antigens are presented to T cells by the leukemia cells, providing a basis for separating the graft-versus- leukemia from graft-versus-host reactions. The current clinical challenge is to devise strategies for separating the graft-versus- leukemia response from graft-versus-host disease. NTTH-HCMIU-IM