TUMOR IMMUNOLOGY. 14 million new cancer cases/year worldwide /50% mortality 10 16 cell division in a lifetime Each of us carries 60 or more girmline mutations.

Slides:



Advertisements
Similar presentations
Cancer—Principles and overview By Robert A. Weinberg
Advertisements

Alterations in the Cell Cycle and Gene Mutations that Cause Cancer
Immune control of human papillomavirus (HPV) associated anogenital disease and potential for vaccination Peter L. Stern Journal of Clinical Virology, 2005.
Introduction to Oncology Dr. Saleh Unit 9 R.E.B, 4MedStudents.com 2003.
Niko Bla ž evi ć Mentor: A. Ž mega č Horvat.  The process of transformation from a normal cell to a cancerous one  Synonym: neoplasia Carcin ogenes.
Evading Immune Responses and Tumor Immunology
Cancer Genetics Is Cancer a Genetic Disease? Cancer is not a classic genetic disease, instead, Genetic background (set-up) has a definite role in cancer.
Immunological aspect of tumor
Cancer Cancer originates in dividing cells –Intestinal lining (colon) –Lung tissue –Breast tissue (glands/ducts) –Prostate (gland) –White blood cells.
Immunity to tumors Tumor antigens
Cancer Biology. 2 Outline 1.How do cancer cells differ from normal cells? Tumor progression Molecular basis for cancer.
Theories of cancer genesis
34 Cancer.
Tumor Immunology Masoud H. Manjili
C22 Cancer and the Immune System Cell births ~ cell deaths; production of new cells is regulated Cells that do not respond to normal growth controls can.
Tumor Immunology: Definitions: -Tumor (neoplasm): unchecked cellular growth. -Two types: 1-Benign: controlled tumor. 2-Malignant: uncontrolled tumor. -Malignant.
Chapter 19 Cancer and the Immune System Dr. Capers.
Cancer Cell cycle, oncogenes and tumour suppressors Jake Turner.
Cancer immunology and immunotherapy. First an aside  Oncogenes and tumor suppressor genes.  Definitions anyone?  Oncogene –  Tumor suppressor gene.
Emily Hodgson Hallmarks of Cancer Immunology Drugs Metastasis.
Viruses to Cancer What is cancer?.
TUMOR IMMUNOLOGY Objectives
Viruses and Cancer.
TUMOR IMMUNOLOGY. MORE THAN 100 VARIOUS TUMOR TYPES MULTISTEP TUMORIGENESIS DYNAMIC CHANGE OF TUMOR GENOME –Genetic instability –Oncogenes – ‘gain of.
Tumor genetics Minna Thullberg
NOTES: CH 18 part 2 - The Molecular Biology of Cancer
3.1.3.A Understanding Cancer What is Cancer.
Chapter 21 Cancer and the Immune System Dr. Capers
Cancer --an Overview  Cell Division  Hormones and Cancer  Malignant Transformation  Angiogenesis and Metastasis  Growth.
Cancer A Disease Resulting from Uncontrolled Cell Growth.
Cancer &Oncogenes. Objectives Define the terms oncogene, proto-oncogenes and growth factors giving examples. Describe the mechanisms of activations of.
بسم الله الرحمن الرحيم. Cancer Origin and Terminology Malignant Transformation of Cells Oncogenes and Cancer Induction Tumor Antigens Immune Responses.
Cancer occurs when there is a loss in the control of the cell cycle. There are many controls of the cell cycle. There are many types of cancer.
TUMOR IMMUNOLOGY. MORE THAN 100 VARIOUS TUMOR TYPES MULTISTEP TUMORIGENESIS DYNAMIC CHANGE OF TUMOR GENOME –Genetic instability –Oncogenes – dominant.
Lecture #10 Aims Describe T cell maturation and be able to differentiate naïve and effector T cells. Differentiate the development and functions of Th1.
By: Sara Ibrahim Tel. # Cancer and The Immune System.
Benign Versus Malignant Tumors
Chapter 20 Tumor Immunology. Introduction Part Ⅰ Tumor antigens Part Ⅱ Immune response to tumors Part Ⅲ Mechanism of tumor escape from immune surveillance.
 Cells that continue to replicate, fail to differentiate into specialized cells, and become immortal. 1. Malignant: A tumor that grows indefinitely and.
Changes in the Eukaryotic Genome By: Sergio Aguilar.
Lecture 11 Immunology Tumor immunology Dr: Dalia Galal.
TUMOR IMMUNOLOGY ARPAD LANYI PhD. MORE THAN 100 TUMOR TYPES Most tumors develop later in life, mechanisms to control tumor development must exist. 14.
Host Defense Against Tumors (Tumor Immunity)
Types of Genes Associated with Cancer
CANCER IMMUNOLOGY Hanggoro Tri Rinonce, MD, PhD Department of Anatomical Pathology Faculty of Medicine, Gadjah Mada University.
Chapter 15.  Immunological tolerance is defined as unresponsiveness to an antigen that is induced by previous exposure to that antigen  Antigens that.
Explain how the immune system of the host responds to the presence of a tumour.
IMMUNOLOGICAL TOLERANCE. BASIC FACTS ABOUT TOLERANCE Tolerance – a state of unresponsiveness specific for a given antigen It is specific (negative) immune.
The Problem of Cancer. What are cancer cells ? Cancerous growth involves unrestrained proliferation (malignancy) and spread (metastasis). Caused by: mutations.
Tumor Immunology. Learning Objectives n n Etiology of cancer n n Mechanisms by which immune system recognize tumors n n Understand tumor escape mechanisms.
Tumor Immunology. Key questions:  How do tumor cells evade the immune system  What are the main immune responses to tumor cells?  What are the potential.
Cancer immunotherapy: an update
Tumor Immunology Masoud H. Manjili
Cancer and the Immune System
Immunological tolerance and immune regulation -- 1
Objectives Introduction Ags expressed by cancer cells
HOST DEFENCE AGAINST TUMORS:
Mechanisms of T Cell Tolerance
بسم الله الرحمن الرحيم 1.
Cancer and the Immune System
The Genetic Basis of Cancer
Alterations in the Cell Cycle and Gene Mutations that Cause Cancer
Immunological memory Topics Immune regulation  T cells
Tumor Immunology Ali Al Khader, MD Faculty of Medicine
Msc clinical immunology
Extracellular Regulation of Apoptosis
Immunology Dr. Refif S. Al-Shawk
Tumor Immunology Ali Al Khader, MD Faculty of Medicine
Carcinogenesis Dr. Mamlook Elmagraby.
Presentation transcript:

TUMOR IMMUNOLOGY

14 million new cancer cases/year worldwide /50% mortality cell division in a lifetime Each of us carries 60 or more girmline mutations not present in parents

MORE THAN 100 VARIOUS TUMOR TYPES MULTISTEP TUMORIGENESIS DYNAMIC CHANGE OF TUMOR GENOME –Genetic instability –Oncogenes – ‘gain of function’ change –Tumor suppressor genes – recessive ‘loss of function’ change PROGRESSIVE TRANSFORMATION –Benign tumor abnormal, but limited growth –Malignant tumor unlimited growth, break basal membranes, invasion –Metastatic tumor seeds new tumors at distant sites. MULTIPLE LIMITING AND INHIBITORY CHECK POINTS –Growth advantage –Selection REGULATORY CIRCUITS –Inherent cell autonomous regulatory mechanisms –Microenvironmental factors Cancer is a result of multiple mutations INDEPENDENT OF THE IMMUNE SYSTEM

Benign or malignant tumors

ACTIVATION OF ONCOGENES Mitogens Growth factor receptors Secondary messengers Tarnscriptional activators Cell cycle genes INACTIVATION OF TUMOR SUPPRESSOR GENES Growth inhibitors Cell cycle inhibitors Programmed cell death genes DNA repair enzymes Unlimited proliferation Sustained angiogenesis Tissue migration and metastasis ACQUIRED PROPERTIES Independent growth factor signals Resistance to growth inhibitory factors Avoid apoptosis Hanahan D és Weinberg RA 2000 Cell Tumor stem cell Tissue cell Malignant cell Malignant transformation

Normal epithelial cells 2 APC mutation Inherited Adenomatous polip 1 Ras mutation Adenomatous polip 2 p53 mutation Colon carcinoma Chromosomal translocation Metastatic colon carcinoma The „multi-hit” model of tumorigenesis Knudson A.G Reaction of the immune system TOLERANCE RECOGNITION Tumor antigens Individual TSA Common TAA CEA TOLERANCEIMMUNE RESPONSE DANGER INNATE/AQUIRED IMMUNITY

Oncogenesis MechanismActionExample Growth promotion Overexpression of growth factor receptors (such as epidermal growth factor, or EGF) making cells more sensitive to growth stimuli c-erb-B2 Increased growth factor signal transduction by an oncogene that lacks the GTPase activity that limits GTP induction of cytoplasmic kinases that drive cell growth ras Overexpression of a gene product by stimulation from an oncogene (such as ras)c-sis Lack of normal gene regulation through translocation of a gene where it is controlled by surrounding genes to a place where it is no longer inhibited c-abl Binding of oncogene product to the nucleus with DNA transcriptional activation to promote entry into the cell cycle c-myc Loss of tumor suppressor gene function Lack of regulation of cell adhesion with loss of growth control through cell interactionAPC Loss of down-regulation of growth promoting signal transductionNF-1 Loss of regulation of cell cycle activation through sequestation of transcriptional factorsRb Loss of regulation of cell cycle activation through lack of inhibition of cell proliferation that allows DNA repair p53 Limitation of Apoptosis Overexpression of gene, activated by translocation, prevents apoptosisbcl-2

OncogeneAssociated Neoplasms c-erb-B2 Breast and ovarian carcinomas ras Many carcinomas and leukemias c-sis Gliomas c-abl Chronic myelogenous leukemia, acute lymphocytic leukemia c-myc Lymphomas BRCA-1 Breast and ovarian carcinomas APC Colonic adenocarcinomas NF-1 Neurofibromas and neurofibrosarcomas Rb Retinoblastomas, osteosarcomas, small cell lung carcinomas p53 Many carcinomas bcl-2 Chronic lymphocytic leukemia, lymphomas VARIOUS ONCOGENES ARE ASSOCIATED WITH DEFINED NEOPLASMS

CHROMOSOMAL TRANSLOCATION IN BURKITT’S LYMPHOMA Uncontrolled proliferation due to the activation of c-myc oncogene EBV induced tumor 8148q-14q+ c-myc CH VH c-myc CH VH

MHC-dependent rejection of tumors

Infective facial tumor in the inbread populations of the Tasmanian devil About 2/3 of Hungary Population half million

THE IMMUNE RESPONSE TO TUMORS Hidden, changing, proliferating, evolving target Immune surveillence –Few non-self antigens –Poorly immunogenic –Recognized by B and T lymphocytes Tolerance induction –Tumor antigens do exist –Recognized primarily by T lymphocytes –Induce tolerance TUMOR ANTIGENS Tumor associated antigens – TA Present also in normal cells Aberrant/disregulated expression in tumor cells Tumor specific antigens – TSA Unique for individual tumors or tumor types IMMUNE SYSTEM Tumor-specific immune responses can be induced Cytotoxic T lymphocytes can eradicate tumors

Tumor antigens and tumor associated antigens

Tumor-specific antigens

Cancer/testis antigens are expressed almost entirely by cancerous cells, showing little or no expression in healthy tissue, with the exception of normal testis, embryonic ovaries and placenta. No MHC expression Many of them X-linked Over 100 in total --- Potential targets for immune therapy

STRUCTURE AND SOURCE OF TUMOR ANTIGENS MUTATED ONCOGENS AND TUMOR SUPPRESSOR GENES –Involved in transformation –Cytosolic novel determinants - no major targets –Cellular proto-oncogenes  oncogene Ras, p53, Abl Point mutation, deletion, chromosomal translocation, viral gene insertion ABERRANTLY OVEREXPRESSED NORMAL CELLULAR PROTEINS –Low/rare expression in normal cell – ignorance by the immune system TUMOR ANTIGENS ENCODED BY GENOMES OF ONCOGENIC VIRUSES –Immunogenic shared viral proteins DNA viruses – Simian virus 40, a polyomavirus that is found in both monkeys and humans. (Large T-antigen, binds and inactivates p53) Herpes, EBV- LMP protein strongly trasforming. Homologue of CD40 Papilloma HPV16 HPV18 RNA viruses – Retroviruses HTLV ONCOFETAL ANTIGENS –Silenced during development  de-repressed in tumor cells –Tumor markers – carcinoembryonic antigen CEA, specific for carcinomas –Alpha-fetoprotein AFP, hepatocellular carcinoma TISSUE-SPECIFIC DIFFERENTIATION ANTIGENS –CD10/CALLA Common Acute Lymphoid Leukemia Antigen, Melanoma

macrophage DS NK/γδ CD4/CD8 PROTECTION ELIMINATION Immunsurveillence EQUILIBRIUMESCAPE Genetic instability Immune selection Treg cells TUMOR CD8 macrophage DS NK/γδ CD4/CD8 METASTASIS ESCAPING TUMOR VARIANTS

Activation of tumor-specific T-cells by DC Cross-presentation

INDUCTION OF A PROTECTIVE ANTI-TUMOR IMMUNE RESPONSE REQUIRES THE COLLABORATION OF DENDRITIC CELLS AND T- LYMPHOCYTES IL-2 IFN  Tumor Ag CROSS PRIMING APOPTOTIC TUMOR CELL DC IL - 12

TUMOR ANTIGENS –Soluble tumor antigens – inhibit recognition on the cell surface –Antigen modulation – antibody dependent internalization –Masking – antibody binds, no effector function –Low immunogenicity –Peptide antigens – mutations affecting Tc or Th epitopes ANTIGEN PRESENTATION –Direct presentation – non professional APC, no MHC class II, no co-stimulatory molecules –Indirect presentation – by professional APC, soluble CD40 and CD40 ligand inhibit CYTOTOXIC T CELL ACTIVITY –MHC – mutation, altered intracellular transport, β2m, locus, allele –Peptide loading – mutation, tumor derived peptides are not presented, TAP APOPTOSIS –Soluble Fas – inhibits Fas ligand-mediated apoptosis TUMOR DERIVED INHIBITORY FACTORS –TGFβ – G1 block, inhibits tumor growth if sensitive  tumors loose their TGFβ receptor –TGFβ inhibits immune cell activation –PGE2 – immune suppression TUMOR DERIVED POTENTIATING FACTORS –Angiogenesis factors – secreted by tumor tissue cells or by immune cells ESCAPE MECHANISMS OF TUMOR CELLS AND TUMOR TISSUES

Manipulation of the immune response by a tumor.

TOLERANCE INDUCTION BY DENDRITIC CELLS SIGNAL 1Tumor antigenYES SIGNAL 2 Tumor cellNO Activated APCYES SIGNAL 3Natural immunityNO InflammationNO Tumor-associated macrophage (upto 40% of non-malignant cells) M1 macrophage: MHCII, CD80, 86 High iNOS, M2 macrphage: arginase +

Many tumors loose expression of HLA class I proteins Loss of HLA class I expression in prostate cancer. Class I moleculed are stained brown. The stain and HLA class I molecules are not seen on the tumor mass but are restricted to lymphocytes infiltrating the tumor and tissue stromal cells

Human epithelial tumours can inhibit the response of lymphocytes expressing NKG2D

Vaccination against human papilloma viruses can prevent cervical cancer HPV is an oncogenic virus causing genital warts women die of cervical cancer each year Almost all cervical and ovarian cancers are HPV positive Preventing chronic HPV infection should prevent cancer

Vaccination of melanoma patients may cause their tumor to regress Rec. virusSynthetic peptide vaccine It is not yet clear when the vaccine would work. Spectrum from remission to no response

Blocking the inhibitory effects of CTLA4 with a human monoclonal antibody. (Ipilimumab) Blocking the PD1/PDL1 interaction with a human monoclonal antibody also works. 2 year survival is over 24% but quite some complications

T-cell responses to tumors can be improved with chimeric Antigen receptors (CARs) Low affinity of TCR (compared to virus spec. T cells) MHC restriction prevents use in the entire population problem solved by Fv Variable fragment of the heavy and light chains of a Tumor-specific antibody mad a single chain Fusion of FV to an intra cell. domain cont. CD28, CD137 and zeta-chain sequences generates strong signal in the absence of costimulation

B cell tumors can be targeted by CARs specific to CD19

AZ AKTÍV TUMOR-SPECIFIKUS IMMUNTERÁPIA LEHETŐSÉGEI A tumor antigének beviteli módja Tumor protein Tumor protein- derived peptide Anti-idiotipe Ab Vírus-tumor genome Plasmid DNA Modified tumor cell Irradiated tumor cell Heat shock protein Modified DC Mocellin S et al. Lancet Oncology 2004 Tumor cell lysate Loaded DC ANTI-TUMOR IMMUNOTHERAPY

Humanized monoclonal antibodies used in the treatment of patients with cancer.

Cytotoxic T-lymphocytes recognize tumor cells Activated cytotoxic T-lymphocytes kill tumor cells CONSEQUENCES OF T-CELL MEDIATED IMMUNITY