Tumor

• A tumor is a local growth of abnormal tissue consisting of genetic-altered transformed cells and a number of other cell types and connective tissue components characteristic of each tumor type.

A fight between immune cells and cancer

But, sometimes we lose

How does cancer arise? How does cancer arise? IIII

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

How do cancer cells differ from normal?

• Clonal in origin

• Deregulated growth and lifespan

• Altered tissue affinity

• Resistance to control via apoptotic signals

• Change in surface phenotype and markers

• Structural and biochemical changes

• Presence of tumour-specific antigens

Molecular Basis of Cancer

Molecular Basis of Cancer

Uncontrolled cell growth

Conversion of proto-oncogenes to oncogenes: • amplification of c-erbB2 in breast cancer• point mutation of c-ras in kidney and bladder cancers• chromosome translocation of c-myc in Burkitt’s lymphoma

Altered tumor-suppressor genes:• P53 mutation in prostate cancer: failure in cell cycle arrest or apoptosis of prostate tumors• Rb mutation: fail to prevent mitosis

Cell GrowthCell Growth

Control of cell growth

Growth-promotingProto-oncogenes

Growth-restrictingTumor-suppressor genes

Tumor Immunology

• Cancer immunosurveilance: immune system can recognize and

destroy nascent transformed cells

• Cancer immunoediting: immune system kill and also induce

changes in the tumor resulting in tumor escape and recurrence (epigenetic changes or Darwinian selection)

Discovery of Immune

surveillance of tumors1. Immune Surveillance-

Macfarlane 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

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.

Immune Recognition of Tumor

Antibodies recognize intact antigens while T cells recognize processed antigens associated with MHC

Examples of tumor antigens-I

Examples of tumor antigens-II

Tumor antigens arise by point mutations in self

proteins

Tumor antigens arise by reactivated genes or overexpressed genes

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

IInduction nduction of of T cell responses to T cell responses to tumortumorss

Cross-priming (cross-presentation) mediated by APCs, ex. DCs

Direct CTL / NK attack

CTL

TUMOUR CELL

Fas (CD95)

FasLTCR

Class I + Ag

Perforin Granzyme B

Antigen-specific tumor killing:

B cells (opsinization & ADCC)

sIg

Tumor

ComplementMacrophage/opsinization

FcRFabFcNK cells & ADCC

Tumor

Antigen-specific Tumor Killing:T Cells

MH

CI

pepti

de

Apoptosis

T cell receptor (TCR)

CD8 Tumor

IFN-Granzyme B

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

Tumor and activated T cells

Two major pathways for TCL: Fas-mediated and perforrin-mediated

Mechanisms of Tumor Mechanisms of Tumor evasionevasion

Tumors w/Fas

Treg infiltrating

Down regulation of the MHC class presentation

pathway• Downregulation of MHC class I expression

is frequently seen in human tumors.• Loss of MHC-I as a mechanism for tumor

escape from CTL-mediated elimination (longitudinal study of melanoma patients)

• Five major HLA altered phenotypes found in tumor tissues (Human Immunol. 2000, 61:65)

The five altered The five altered phenotypesphenotypes

Normal A1A2B8B35Cw7Cw4

1. Total loss -2. Haplotype loss A1B8Cw7

3. Locus loss A1A2B8B35

4. Allelic loss A2B8B35Cw7Cw4

5. Compound phenotype A1

(Human Immunol. 2000, 61:65)

Resistance to killing

• Defective Fas pathway

• Resistance to Granzyme B

• Fas-L and Neutrophil

Cytotoxic T cells

Innate immunity

Three Es of Immunoediting

CTL

CTL

NKT

NK

CD4

NK CTLCD4

NKCTL

Elimination Equilibrium Escape

Genetic instability / tumour heterogeneity

Immunoediting of Cancer

How does MM evade the immune response?

myeloma cancer cell

Broken up to release antigens

APC

APC recruits CTL specific for myeloma Ag

T

T

T

TT

T cells recognise and destroy other

cancer cells

MM cell release factors which

‘turn off’ T cells

The Strategies for Cancer The Strategies for Cancer TherapyTherapy

The best scenario – Kill all the tumor cells without destroy others in the body

1. Surgery – remove tumor cells & tissues physically 2. Radiotherapy – non-selective, strong side effect3. Chemotherapy - non-selective, strong side effect4. Gene therapy – relatively selective5. Targeted therapy - relatively selective6. Immunotherapy => manipulate an immune

response against tumor cells but not normal cells => quite selective

Tumor vaccines-Targeting DCs

Types of Tumor Vaccines

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

SUMMARY1. 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.