Tumor Immunology

Wirsma Arif HarahapSurgical Oncologist

Surgery Department Andalas Medical School

Immune System

A complex of lymphoid organs

• highly specialized cells• circulatory system

separate from blood vessels

Immune System• Lymphatic vessels form a

circulatory system that operates in close partnership with blood circulation

• Carries lymph, a fluid that contains WBCs (chiefly lymphocytes)

• Lymph nodes provide “meeting grounds”

Four Primary Functions

• Recognition of self– self-tolerance– immunological

privilege• Immunosurveillance• Intracellular hormones• Defense against infection

BacteriaTubercule bacillusStaphylococci

FungiCandida albicans

VirusInfluenzaPolio mellitus

Parasites

TapewormsMalariaHelminths

Role of the immune system is to protect

from:

Eosinophil

Monocyte

Macrophage

Neutrophil

Basophil

Origin of cells involved in the immune response

Haemopoietic stem cell

B cellThymusNK cell

Dendritic cell

Mast cell

Plasmacell

CD4T cell

Myeloid progenitor

Lymphocyteprogenitor

CD8T cell

3 Types of Actions of the Immune System

1. Mechanical

2. Non-specific (innate immunity)

3. Specific ( adaptive immunity )

Overview of immune responses

Interactions between innate and& adaptive immunity

1. Innate immunity => Ag presentation (by Dendritic cells)

2. Adaptive immunity => Ag recognition (by T & B lymphocytes)

Evidence for the role of immune system in tumor rejection

Spontaneous regression Infiltration of tumors by lymphocytes and

macrophages Regression of metastases after removal of

primary tumor Regression after chemotherapy Lymphocyte proliferation in draining lymph

nodes Higher incidence of cancer after

immunosuppression/immunodeficiency (AIDS, neonates, aged, transplant patients)

Association between immunodeficiency and cancer

Association between immunodeficiency and cancer

primary (inherited) immunodeficiency

lymphomas

Burkitt’s lymphoma malaria

secondary (acquired) immunodeficiency

lymphoma, cervical cancer, liver cancer, skin cancer, Kaposi’s sarcoma.

autoimmunity lymphoma

malignancycause of immuno-deficiency

Tumors stimulate an immune response

Tumors stimulate an immune response

Animals can be immunized against tumorsImmunity is transferable from immune to

naïve animalsTumor specific antibodies and cell have

been detected in humans with some malignancies

Animals can be immunized against tumorsImmunity is transferable from immune to

naïve animalsTumor specific antibodies and cell have

been detected in humans with some malignancies

Etiology Of Tumor1) Inherited : Expression of inherited oncogene e.g. viral gene incorporated into host gene

2) Viral: - Human papilloma, herpes type 2, HBV, EBV (DNA) - Human T-cell leuckemia virus (RNA)

3) Chemical: - Poly cyclic hydrocarbons cause sarcomas - Aromatic amines cause mammary carcinoma - Alkyl nitroso amines cause hepatoma

4) Radiological: Ultraviolet & ionizing irradiation

5) Spontaneous: failure in the cellular growth control

Tumor Associated Antigens !) Viral Antigen : a- Viral proteins and glycoproteins b- New antigens produced by virally infected host cells under control of viral nucleic acid

2) Tumor specific antigens : - Tumor cells develop new antigen specific to their carcinogens

3) Tumor specific transplantation antigens : - Tumor cells express new MHC antigens due to alteration of normally present MHC antigens

Tumor Associated Antigens

4) Oncofetal antigens:

a- Carcino-embryonic antigens (CEA) - Normally expressed during fetal life on fetal gut - Reappearance in adult life: GIT, pancreas, biliary system and cancer breast

b- Alpha fetoprotein: - Normally expressed in fetal life - Reappearance in adult life; hepatoma

Immunity against tumorImmunity against tumor

All components, specific and nonspecific, humoral and cellular affect

tumor progression and growth

All components, specific and nonspecific, humoral and cellular affect

tumor progression and growth

Antigens expressed on tumor cells

Major HistocompatabilityComplex antigens

TSTA

TATA

TSTA : unique to a tumor Play an important role in tumor rejection.TATA : shared by normal and tumor cells

Tumor-associated developmental Ag (TADA)Tumor-associated viral Ag (TAVA)

Tumor-specific transplantation Ag

Tumor-associatedtransplantation Ag

Tumor associated transplantation antigens: shared Ag on virally induced tumors

Tumor associated transplantation antigens: shared Ag on virally induced tumors

Discovery of tumor specific transplantation antigens, TSTADiscovery of tumor specific transplantation antigens, TSTA

Tumor-Associated Developmental Ags

Found on cancer cells and on fetal cells. Do not trigger anti-tumor immunity. Used in diagnosis.

Alpha-fetoprotein(AFP) Cancers of liver Carcinoembryonic Ag (CEA) colorectal cancer Breast cancer CA 15-3 Ovarial cancer CA 15-5

Escape from immunosurveillanceEscape from immunosurveillance

Lack of Neo-antigens

Escape from immunosurveillanceEscape from immunosurveillance

Lack of Neo-antigens

Escape from immunosurveillanceEscape from immunosurveillance

Lack of class I MHC

Escape from immunosurveillanceEscape from immunosurveillance

Tumors secreteImmunosuppressive molecules

Escape from immunosurveillanceEscape from immunosurveillance

Tumors shed their neo-antigens

Tumors escape the action of CTL by not expressing B7 which provides 2nd signal involved in T cell activation

tumor

CTL

tumor Ag

Class I MHC

B7

CD28

Tumors may fail to express costimulatory molecules involved in T cell activation.

Utility of Immunology in

Cancer Treatment

Use of tumor associated antigens

Raise monoclonal antibodiesUse antibodies for diagnosisUse antibodies for therapy

Stimulate the in vivo specific responseSpecific active treatmentSpecific passive treatmentAdjuvant therapy to augment specific

immunity

Use of tumor associated antigensmonoclonal antibodies

Use of tumor associated antigensmonoclonal antibodies

Monoclonal antibodies:use as a diagnostic tool

Monoclonal antibodies:use as a diagnostic tool

Immunotherapy of tumorsImmunotherapy of tumors

non- specific

BCG, Propionibacterium acne, levamisole, etc.

killed tumor cells, purified or recombinant Ag

specific

active immunotherapy

LAK cells, cytokinesnon-specific

antibodies alone or conjugated with other agent, activated T cellsspecific

passive immunotherapy

Non-specific immunotherapyNon-specific immunotherapy

activate macrophages and NK cells

IFN-, IFN-, IFN-, IL-2, TNF-

cytokines

interferon productionpyran, poly I:C

synthetic molecules

activate macrophages and NK cells (via cytokines)

BCG, P. acnes, muramyl dipeptide

bacterial products

increased expression of class-I MHC, possible anti tumor effect

remission of hairy cell leukemia, weak effect on carcinomas

IFN

IFNincreased expression of class-I MHC, Tc and NK cell activation

remission of ovarian carcinoma

IL-2T cell proliferation and activation, NK cell activation

remission in renal cell carcinoma and melanoma

TNFmacrophage and lymphocyte activation

reduction in malignant ascites

Cytokine immunotherapyCytokine immunotherapy

Active Immunization: The host actively elicits an immune response. Specific

Vaccination with viral Ags: e.g. Hepatitis B virus Human Papilloma virus (HPV)

Thank You