Transcript Immune responses to tumors

Introduction of Tumor Immunology
• Bei-Chang Yang (楊倍昌), Ph.D.
Department of Microbiology & Immunology
ext 5637; [email protected]
• Pin Ling (凌 斌), Ph.D.
ext 5632; [email protected]
• 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)
Goals of This Course
•
Build up the concepts of Tumor Immunology
•
Learn the current development of Tumor
Immunology, including immunotherapy &
cancer vaccines.
•
Not only deliver the knowledge but exercise
thinking
Outline of Lecture Topics
•
Discuss the interactions between the immune
system and the cancer development, covering the
following topics:
(1)
Basic concepts of tumor immunology
(2) Immunosurveillance and immunoediting of cancer
(3) Mechanisms of immune evasion by tumors
(4) Cancer vaccine development Cancer immunotherapy
(5) Inflammation & Cancer, and other topics
Lectures & Paper Discussion
•
Run the class with “Lectures” and “Paper discussion”
•
Lectures deliver the basic concepts of fields.
•
Paper discussion focuses on the latest articles
related to specific topics.
•
Research Project discussion
- Choose a type of cancer as the topic of
cancer immunotherapy
- Apply the knowledge from this course to
cancer treatment
Paper & Project Discussion
1.
4 sections of Paper discussion and 2
sections of Project discussion
2. 2 paper presentations each time for 4
sections (Total 9 students)
3. 2 project presentations each time for
2 sections (Total 4 groups)
4. Each presentation: 40 min talk and 10 min
discussion
Evaluation
1. Attendance – 60%
2. Paper & Project Presentation – 20 %
3. Class performance – 20%
Overview of Tumor Immunology
1. Tumorigenesis
2. Discovery of the protective immune
response against tumors.
3. T cells recognize specific antigens on
tumors
4. Tumors can escape in many ways
5. Immunotherapy for tumors
How does cancer arise?
Dysregulated cell growth & proliferation
=> Transformation
A clone of cells expanding indefinitely
=> A tumor
Tumor cells => the body and cause diseases
=> 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
The Strategies for Cancer Therapy
The best scenario – Kill all the tumor cells without
destroy others in the body
1.
2.
3.
4.
5.
6.
Surgery – remove tumor cells & tissues physically
Radiotherapy – non-selective, strong side effect
Chemotherapy - non-selective, strong side effect
Gene therapy – relatively selective
Targeted therapy - relatively selective
Immunotherapy => manipulate an immune response
against tumor cells but not normal cells
=> quite selective
Key Concepts in Tumor immunity
1. Tumors express Ags that are recognized as foreign by
the host immune system.
2. Immune responses frequently fail to prevent the
growth of tumors.
3. The immune system can be activated by external
stimuli to effectively kill tumor cells and eradicate
tumors.
4. Various strategies have been developing to enhance the
anti-tumor immune responses.
Discovery of Immune
surveillance of tumors
Discovery of Immune
surveillance of tumors
1. Immune SurveillanceMacfarlane Burnet in 1950s
2. Use syngeneic mouse strain
=> Transplantation exp
3. Immunization w/ irradiated
tumor X cells protects a
syngeneic mouse w/ live X tumor
cells but not Y tumor cells.
4. Antigens expressed by tumors,
termed tumor antigens.
5. Defense against tumors is
mainly mediated by T cells
Immune surveillance of tumors-II
Identification of tumor Ags by CTLs
Examples of
tumor antigensI
Examples of tumor antigens-II
Tumor antigens arise by point
mutations in self proteins
Tumor antigens arise by reactivated
genes or overexpressed genes
Induction of T cell responses to tumors
Cross-priming (cross-presentation) mediated by APCs, ex. DCs
Immune responses to tumors
1. Adaptive immune responses to tumors:
a. CD8 CTLs are the key players on the killing effect of
tumors.
b. CD4 T helper cells => cytokines => CTLs
c. Abs => activating complements or Ab-dep cell-med toxicity
=> preventing oncogenic viruses
2. Innate immune responses to tumors:
a. NK cells kill many types of tumor cells that have reduced
class-I but express ligands for activating NK cells.
b. Macrophages => Ab-med phagocytosis
=> Cytokines (TNF-a), ROS, & NO
Overview of Tumor Immunology
1. Tumorigenesis
2. Discovery of the protective immune
response against tumors.
3. T cells recognize specific antigens on
tumors
4. Tumors can escape in many ways
5. Immunotherapy for tumors
Overview of Tumor Immunology
1. Tumorigenesis
2. Discovery of the protective immune response
against tumors.
3. T cells recognize specific antigens on tumors
4. Tumors can escape in many ways
5. Immunotherapy for tumors
Q: Why tumors still develop in the
body if the immune system has the
ability to recognize them?
 Tumors develop many ways to escape
from immune attacks
Mechanisms of Tumor evasion
Treg infiltrating
Tumors w/Fas
Tumor loss of MHC-I as a evasion
mechanism
Immunoediting
of Cancer
Dunn et al. Nature Reviews
Immunology 6, 836–848 (November
2006) | doi:10.1038/nri1961
The progress in Immunology & Molecular
Biology in past few decades make possible
to manipulate the immune responses against
tumors.
 Enhancing Tumor Immunogenicity
 Enhancing Anti-Tumor Responses
Overview of Tumor Immunology
1. Tumorigenesis
2. Discovery of the protective immune
response against tumors.
3. T cells recognize specific antigens on
tumors
4. Tumors can escape in many ways
5. Immunotherapy for tumors
Tumor vaccines-Targeting DCs
Types of Tumor Vaccines
Enhancement of tumor
immunogenicity
Immunotherapy with cytokine
gene-transfected tumor cells
Systemic cytokine therapy for tumors
Passive
Immunotherapy
for tumors
Adoptive cellular therapy
Therapy with Anti-tumor
Monoclonal Abs
Approved Anti-tumor mAb
SUMMARY
1. Cancer is a complex and progressive genetic disease.
2. Tumors express Ags that could be recognized by the
immune system. But some tumors are weakly
immunogenic and the immune system often fails to
eradicate them.
3. Cancer from clinical cases usually represents the
leading of cancer development over the anti-cancer
immune responses.
4. The imperative issue in the field of tumor immunology is
to improve the capability of immune defenses to fight
cancer.
Paper Discussion on March 18
SCIENCE VOL 319 11 JANUARY 2008
Recognition of a Ubiquitous Self Antigen by Prostate
Cancer–Infiltrating CD8+ T Lymphocytes
Peter A. Savage,1 Keith Vosseller,2 Chulho Kang,3 Kevin Larimore,4 Elyn
Riedel,5Kathleen Wojnoonski,1 Achim A. Jungbluth,6 James P. Allison1*
Nature. 2007 Jan 4;445(7123):106-10. Epub 2006 Nov 19
A human colon cancer cell capable of initiating tumour
growth in immunodeficient mice.
O’Brien CA, Pollett A, Gallinger S, Dick JE.
Division of Cell and Molecular Biology, University Health Network, Toronto, Ontario,
M5G 1L7, Canada.
The End & Thank you