Introduction of Tumor Immunology Pin Ling ( 凌 斌 ), Ph.D. ext 5632; References: 1. Tumor Immunology and Cancer Vaccines (Samir Khleif, Publisher: Springer; 1st edition 2005) 2. Cancer Immunotherapy-Advances in Immunology, Vol. 90 (James Allison, Glen Dranoff; Publisher: Academic Press 2006) 3. “Cancer Immunology and Immunotherapy” in Current Topics in Microbiology and Immunology, Vol 344, 2011

Goals 1. Build up the Concepts of “Tumor Immunology”. 2. Discuss the “Current Progress” of Tumor Immunology, including Tumor-immune system interaction, Immunotherapy, & Cancer Vaccines. 3. Run the course with “Lectures”, “Paper Discussion”, & “Research Proposal”

Outline of Lecture Topics Discuss the interactions between the immune system and the cancer development, covering the following topics: (1)Basic Tumorigenesis (2)Inflammation & Cancer (3)Immunosurveillance and Immunoediting of Cancer (4)Mechanisms of Immune Evasion by Tumors (5)Cancer Vaccine Development & Cancer Immunotherapy

Lectures, Paper Discussion & Research Proposal 1.“Lectures” deliver the basic concepts of fields. 2.“Paper discussion” focuses on the latest articles related to specific fields. 3.Research Project Discussion - Choose a type of cancer as the topic of cancer immunotherapy or other tumor immunology topics - Apply the knowledge from the basic science to the cancer treatment 4. Not only deliver the “Knowledge” but exercise “Problem-solving” & “Thinking”

1.4 sessions of Paper discussion and 2-3 sessions of Project discussion 2.2 presentations for each paper discussion (depends on total students) 3. Each paper presentation: min talk and 10 min discussion Paper & Project Discussion Team work is the key!  Everyone should get involved in paper and project discussion

1. Propose a research project to study topics in Tumor Immunology or Cancer immunotherapy 2. Abstract presentation: 20 min/each team and 5-10 min discussion - Prepare one-page written abstract & 20 min talk to present your team’s idea - Short Rationale (Background), Main goal, approaches (specific aims), & potential problems. Research Project Discussion

3. Full proposal presentation: min talk and 10 min discussion - Like Abstract, extend each parts, Rationale, Specific aims, & Alternatives (for potential problems) - Turn in a written full proposal (around 10 pages) Research Project Discussion

1. Exercise “Scientific Approaches” - How to translate your scientific knowledge into scientific advancement & clinical applications 2. Emphasize on Originality, Logic Thinking & Extensiveness (1) Identify a key problem or challenge in the field (2) Form a hypothesis (Originality & Novelty) (3) Layout the approaches (specific aims) (Logic Thinking) (4) Alternatives (potential problems) (Comprehensiveness) 3. Avoid to repeat an approach from Cancer A to Cancer B Keys to a research proposal If you are still unclear,  Check with your advisor or me after class  Check post-docs or senior PhD students in your lab

Reading (Papers) Writing (Proposal) Listening (Lectures) Speaking (Presentation) InputsOutputs Key Elements in Learning

Evaluation 1. 上課出席率 (Attendance) 50% 2. 專題報告 (Paper, Research Project Discussion, and Written Proposal) 30% 3. 課堂表現 (Class Performance) 20%

1.Tumorigenesis 2.Overview of the immune system 3.T cells recognize specific antigens on tumors 4.Tumors can escape in many ways 5.Manipulate the immunity against tumors 6.Cancer Immunotherapy Overview of Tumor Immunology

How does cancer arise? Dysregulated cell growth & proliferation => Transformation A clone of cells expanding indefinitely => A tumor (continuously evolved) Tumor cells => the body and cause diseases (Metastasis) => Cancer

How does cancer arise? II Q: What causes dysregulated cell growth & proliferation? Intrinsic factors - Genetic mutations on Oncogenes & Tumor suppressor genes Environmental factors – Radiation, Carcinogens Microbial infections – Viruses (viral oncogenes) Bacteria

Cancer Hallmarks 2000 vs 2011

The Strategies for Cancer Therapy The best scenario –Kill all the tumor cells without destroying normal cells in the body 1.Surgery – remove tumor cells & tissues physically 2.Radiotherapy – non-selective, strong side effect 3.Chemotherapy - non-selective, strong side effect 4.Gene therapy – relatively selective 5.Targeted therapy - relatively selective => successful cases growing 6.Immunotherapy => manipulate an immune response against tumor cells but not normal cells

1.Tumorigenesis 2.Overview of the immune system 3.T cells recognize specific antigens on tumors 4.Tumors can escape in many ways 5.Manipulate the immunity against tumors 6.Cancer Immunotherapy Overview of Tumor Immunology

Key concepts about immunity-I 1. The immune system has evolved to (1) Protect against the invading pathogens (or foreign substances) and to (2) Maintain tissue homeostasis (damaged cells or cancer). Meanwhile, microbes (outside) and tumors (inside) have evolved to survive in the host. 2. The immune system (in vertebrates) consists of (1) Innate immunity and (2) Adaptive immunity => An integrated system of host defense => Cells & molecules function cooperatively Antigen-presenting cells => Lymphocytes => Effector cells 3. Innate immunity is evolutionally the more conserved host defense system: - Existed in both Invertebrates & Vertebrates - Provides the first line of defenses against infections - “Activates” and “Programs” adaptive immune responses

Key concepts about immunity-II 5. Adaptive immunity evolved later: - Existed only in Vertebrates - Provides the more potent and diverse defenses against infections - Develops as a response to infection and adapts to the infection 6. The immune system may fail => Immunodeficiency, Hypersensitivity, & Autoimmune diseases. 7. Normal immune responses can be obstacles in medical cases, e.g., organ transplantation Better Understanding of Immunology  Help manipulate immune responses  Solve the medical problems

Overview of immune responses-I

PRRs for sensing infectious & endogenous signals 1. PRRs (Pattern Recognition Receptor) for: (1) PAMPs from pathogens (2) DAMPs (Danger Associated Molecular Patterns) from host cells 2. Deregulated immune responses to these stimuli leading to Infectious diseases Autoimmune disorders Allergy “Cancer development”

Interactions between innate and & adaptive immunity 1. Innate immunity => Ag presentation (by Dendritic cells) 2. Adaptive immunity => Ag recognition (by T & B lymphocytes)

Immune Recognition of Tumors 1. Syngenic mouse strain => the immune response against tumors 2. Immunization w/ irradiated tumor X cells protects a syngenic mouse w/ live tumor X cells but not tumor Y cells. 3. Antigens expressed by tumors, termed Tumor Antigens.

Q: How do tumor antigens (Ags) arise?  Tumor Ags arise from many ways: (1) Mutations or translocations on self genes (2) Abnormal expression of self gene products (3) Reactivation of germ cell genes (4) Viral oncogenes

Tumor antigens arise by point mutations in self proteins

Tumor antigens arise by reactivated genes or overexpressed genes

Examples of tumor antigens

Identification of tumor antigens recognized by tumor-specific CTLs

Types of tumor antigens recognized by CTLs

Induction of T cell responses to tumors

Natural Killer (NK) Cells 1. Another weapon for anti- Tumor immunity 2. Kill tumor cells losing MHC-I

Q: Why tumors still develop in the body if the immune system has the ability to recognize them?  Most clinical cancer cases represent the situation that Tumors outsmart the host immune system  Tumors develop many ways to escape from immune attacks  Tumors use immune cells to help their development

Mechanisms of Tumor evasion

Tumor loss of MHC-I as a evasion mechanism

Paradoxical roles of the immune system in cancer development 1. Mechanisms against cancer development: (1) Cellular immunity- T, NK, & Other innate immune cells (2) Humoral immunity- Cytokines, Abs,..etc 2. Mechanisms promoting cancer development: (1) Inflammation => angiogenesis & tissue remodeling (2) Enhance survival pathways (NF-kB) (3) Suppression of anti-tumor immune responses

The progress in Immunology & Molecular Biology in past decades make possible to manipulate the immune responses against tumors.  Enhance Tumor Immunogenicity  Enhance CTLs & NK Killing ability  Change Tumor Microenvironment

Development of Tumor Vaccines

Types of Tumor Vaccines

Strategies for enhancing immune responses to tumors

Immunotherapy w/ Cytokine Gene-Transfected Tumor Cells

Systemic Cytokine Therapy for Tumors

Adoptive Cellular Therapy Ex vivo activate CTLs or NK cells

Monoclonal Abs against tumors

Approved Anti-Tumor Monoclonal Ab

The End & Thank you

Strategies for enhancing immune responses to tumors

Figure part 2 of 3

Figure part 3 of 3

Discovery of Immune recognition of tumors 1. Use syngenic mouse strain => the immune response against tumors 2. Immunization w/ irradiated tumor X cells protects a syngenic mouse w/ live tumor X cells but not tumor Y cells. 3. Antigens expressed by tumors, termed Tumor Antigens.

Downloaded from: StudentConsult (on 3 March :47 PM) © 2005 Elsevier

Downloaded from: StudentConsult (on 3 March :47 PM) © 2005 Elsevier

The Interface between innate and adaptive immunity 1. Innate immunity => Ag presentation (by dendritic cells) 2. Adaptive immunity => Ag recognition (by T & B lymphocytes)

1. Human immune system: (1)Innate immunity (2)Adaptive immunity 2. Serve two functions: (1)Protect against infection (2)Cell & Tissue Homeostatsis Overview of immune responses-II