By:By:Sara IbrahimSara Ibrahim

Tel. # 122515975Tel. # 122515975E-mail: sursur555@hotmail.comE-mail: sursur555@hotmail.com

Cancer and The Immune System

Cancer and The Immune Response

Cancer and The Immune Response

IntroductionIntroduction Ags expressed by cancer cellsAgs expressed by cancer cells Nature of immune responseNature of immune response How cancer evades immune How cancer evades immune

systemsystem

Cancer Introduction

Cancer Introduction

Uncontrolled growth produces a tumor or Uncontrolled growth produces a tumor or neoplasm.neoplasm.

A tumor that grows indefinitely and often A tumor that grows indefinitely and often spreads (metastasis) is called spreads (metastasis) is called malignantmalignant----also called cancer.also called cancer.

A tumor that is not capable of indefinite A tumor that is not capable of indefinite growth----growth----benign.benign.

Cell GrowthCell Growth

Control of cell growth

Growth-promotingProto-oncogenes

Growth-restrictingTumor-suppressor genes

Molecular Basis of CancerMolecular Basis of Cancer

Uncontrolled cell growth

Proto-oncogenesTumor-suppressor genes

MutationsRadiationChemicalsVirus

Types of Cancer based on the tissue affectedTypes of Cancer based on the tissue affected CarcinomaCarcinoma: Cancer of endo or ectoderm : Cancer of endo or ectoderm

e.g. Skin or epithelial lining of organse.g. Skin or epithelial lining of organs SarcomasSarcomas: Cancer of mesoderm e.g. bone: Cancer of mesoderm e.g. bone Leukemias and LymphomasLeukemias and Lymphomas: Cancers of : Cancers of

hematopoietic cellshematopoietic cells

Types of cancers based on etiologic agentTypes of cancers based on etiologic agent Chemically-induced tumorsChemically-induced tumors

Each tumor induced by a carcinogen (benzopyrene) Each tumor induced by a carcinogen (benzopyrene) injected at various sites expresses a unique Ag.injected at various sites expresses a unique Ag.

Thus difficult to develop vaccine.Thus difficult to develop vaccine.

Virus-induced tumorsVirus-induced tumors Tumors induced by same virus express same tumor Ag.Tumors induced by same virus express same tumor Ag. Induce a strong immune response.Induce a strong immune response.

e.g. Gardasil – Human Papilloma Virus (HPV) induced e.g. Gardasil – Human Papilloma Virus (HPV) induced cervical cancercervical cancer

UV-induced tumorsUV-induced tumors UV radiation--->melanomasUV radiation--->melanomas

Evidence for the role of immune system in tumor rejection

Evidence for the role of immune system in tumor rejection

Spontaneous regressionSpontaneous regression Regression of metastases after removal of Regression of metastases after removal of

primary tumorprimary tumor Infiltration of tumors by lymphocytes and Infiltration of tumors by lymphocytes and

macrophagesmacrophages Lymphocyte proliferation in draining lymph Lymphocyte proliferation in draining lymph

nodesnodes Higher incidence of cancer after Higher incidence of cancer after

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

The immune response to foreign antigens consists of The immune response to foreign antigens consists of humoral (eg, antibodies) and cellular mechanisms. humoral (eg, antibodies) and cellular mechanisms. Most humoral responses cannot prevent tumor growth. Most humoral responses cannot prevent tumor growth. However, effector cells, such as T cells, macrophages, However, effector cells, such as T cells, macrophages, and natural killer cells, have relatively effective and natural killer cells, have relatively effective tumoricidal abilities. Effector cell activity is induced by tumoricidal abilities. Effector cell activity is induced by cells that present tumor-specific antigens (TSAs) or cells that present tumor-specific antigens (TSAs) or tumor-associated antigens (TAAs) on their surface tumor-associated antigens (TAAs) on their surface (these cells are called antigen-presenting cells) and is (these cells are called antigen-presenting cells) and is supported by cytokines (eg, interleukins, interferons. supported by cytokines (eg, interleukins, interferons. Despite the activity of effector cells, host Despite the activity of effector cells, host immunoreactivity may fail to control tumor occurrence immunoreactivity may fail to control tumor occurrence and growth.and growth.

Antigens expressed on tumor cellsAntigens 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 AgTumor-associatedtransplantation Ag

Tumor-Associated Developmental AgsTumor-Associated Developmental Ags

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

Alpha-fetoprotein(AFP) Cancers of liverAlpha-fetoprotein(AFP) Cancers of liver Carcinoembryonic Ag (CEA) colorectal Carcinoembryonic Ag (CEA) colorectal

cancercancer

Other Tumor associated antigensOther Tumor associated antigens Differentiation Ags: B cells produce surface Ig. Differentiation Ags: B cells produce surface Ig.

B cell tumors have sIgB cell tumors have sIg

Melanomas and melanocytes express MART-1Melanomas and melanocytes express MART-1 Overexpression of Ag on tumors compared to Overexpression of Ag on tumors compared to

normal cells e.g. In breast cancer, HER2/neunormal cells e.g. In breast cancer, HER2/neu Ags expressed on male germ cells and melanoma Ags expressed on male germ cells and melanoma

e.g. MAGE-1e.g. MAGE-1

Cellular ImmunityCellular Immunity

The T cellThe T cell is the primary cell responsible for direct is the primary cell responsible for direct recognition and killing of tumor cells. T cells carry out recognition and killing of tumor cells. T cells carry out immunologic surveillance, then proliferate and destroy immunologic surveillance, then proliferate and destroy newly transformed tumor cells after recognizing TAAs. newly transformed tumor cells after recognizing TAAs. The T-cell response to tumors is modulated by other cells The T-cell response to tumors is modulated by other cells of the immune system; some cells require the presence of of the immune system; some cells require the presence of humoral antibodies directed against the tumor cells humoral antibodies directed against the tumor cells (antibody-dependent cellular cytotoxicity) to initiate the (antibody-dependent cellular cytotoxicity) to initiate the interactions that lead to the death of tumor cells. In interactions that lead to the death of tumor cells. In contrast, suppressor T cells inhibit the immune response contrast, suppressor T cells inhibit the immune response against tumors.against tumors.

Cytotoxic T lymphocytesCytotoxic T lymphocytes (CTLs) recognize antigens (CTLs) recognize antigens on target cells and lyse these cells. These antigens on target cells and lyse these cells. These antigens may be cell surface proteins or may be intracellular may be cell surface proteins or may be intracellular proteins (eg, TAAs) that are expressed on the surface proteins (eg, TAAs) that are expressed on the surface in combination with class I major histocompatibility in combination with class I major histocompatibility complex (MHC) molecules. Tumor-specific CTLs complex (MHC) molecules. Tumor-specific CTLs have been found with neuroblastomas; malignant have been found with neuroblastomas; malignant melanomas; sarcomas; and carcinomas of the colon, melanomas; sarcomas; and carcinomas of the colon, breast, cervix, endometrium, ovary, testis, breast, cervix, endometrium, ovary, testis, nasopharynx, and kidney.nasopharynx, and kidney.

Natural killer (NK) cellsNatural killer (NK) cells are another population of effector are another population of effector cells with tumoricidal activity. In contrast to CTLs, NK cells cells with tumoricidal activity. In contrast to CTLs, NK cells lack the receptor for antigen detection but can still recognize lack the receptor for antigen detection but can still recognize normal cells infected with viruses or tumor cells. Their normal cells infected with viruses or tumor cells. Their tumoricidal activity is termed “natural” because it is not induced tumoricidal activity is termed “natural” because it is not induced by a specific antigen. The mechanism by which NK cells by a specific antigen. The mechanism by which NK cells discriminate between normal and abnormal cells is under study. discriminate between normal and abnormal cells is under study. Evidence suggests that class I MHC molecules on the surface of Evidence suggests that class I MHC molecules on the surface of normal cells inhibit NK cells and prevent lysis. Thus, the normal cells inhibit NK cells and prevent lysis. Thus, the decreased level of class I molecule expression characteristic of decreased level of class I molecule expression characteristic of many tumor cells may allow activation of NK cells and many tumor cells may allow activation of NK cells and subsequent tumor lysis.subsequent tumor lysis.

MacrophagesMacrophages can kill specific tumor cells can kill specific tumor cells when activated by a combination of factors, when activated by a combination of factors, including lymphokines (soluble factors including lymphokines (soluble factors produced by T cells) and interferon. They are produced by T cells) and interferon. They are less effective than T-cell–mediated cytotoxic less effective than T-cell–mediated cytotoxic mechanisms. Under certain circumstances, mechanisms. Under certain circumstances, macrophages may present TAAs to T cells and macrophages may present TAAs to T cells and stimulate tumor-specific immune response.stimulate tumor-specific immune response.

Dendritic cellsDendritic cells are dedicated antigen-presenting are dedicated antigen-presenting cells present in barrier tissues (eg, skin, lymph cells present in barrier tissues (eg, skin, lymph nodes). They play a central role in initiation of nodes). They play a central role in initiation of tumor-specific immune response. These cells tumor-specific immune response. These cells take up tumor-associated proteins, process them, take up tumor-associated proteins, process them, and present TAAs to T cells to stimulate the and present TAAs to T cells to stimulate the CTL response against tumor. The presence of CTL response against tumor. The presence of dendritic cells in tumor tissues correlates with dendritic cells in tumor tissues correlates with improved prognosis.improved prognosis.

LymphokinesLymphokines produced by immune cells produced by immune cells stimulate growth or induce activities of stimulate growth or induce activities of other immune cells. Such lymphokines other immune cells. Such lymphokines include IL-2, also known as T-cell growth include IL-2, also known as T-cell growth factor, and the interferons. IL-12 is factor, and the interferons. IL-12 is produced by dendritic cells and specifically produced by dendritic cells and specifically induces CTLs, thereby enhancing antitumor induces CTLs, thereby enhancing antitumor immune responses.immune responses.

Regulatory T cellsRegulatory T cells are normally present in are normally present in the body and help prevent autoimmune the body and help prevent autoimmune reactions. They are produced during the reactions. They are produced during the active phase of immune responses to active phase of immune responses to pathogens and limit the strong immune pathogens and limit the strong immune response that could damage the host. response that could damage the host. Accumulation of these cells in cancers Accumulation of these cells in cancers inhibits antitumor immune responses.inhibits antitumor immune responses.

Humoral ImmunityHumoral Immunity

In contrast to T-cell cytotoxic immunity, humoral In contrast to T-cell cytotoxic immunity, humoral antibodies do not appear to confer significant antibodies do not appear to confer significant protection against tumor growth. Most antibodies protection against tumor growth. Most antibodies cannot recognize TAAs. Regardless, humoral cannot recognize TAAs. Regardless, humoral antibodies that react with tumor cells in vitro have antibodies that react with tumor cells in vitro have been detected in the sera of patients with various been detected in the sera of patients with various tumors, including Burkitt's lymphoma; malignant tumors, including Burkitt's lymphoma; malignant melanoma; osteosarcoma; neuroblastoma; and melanoma; osteosarcoma; neuroblastoma; and carcinomas of the lung, breast, and GI tract.carcinomas of the lung, breast, and GI tract.

Cytotoxic antibodies are directed against surface antigens Cytotoxic antibodies are directed against surface antigens of tumor cells. These antibodies can exert anti-tumor of tumor cells. These antibodies can exert anti-tumor effects through complement fixation or by serving as a flag effects through complement fixation or by serving as a flag for destruction of tumor cells by T cells (antibody-for destruction of tumor cells by T cells (antibody-dependent cell-mediated cytotoxicity). Another population dependent cell-mediated cytotoxicity). Another population of humoral antibodies, called enhancing antibodies of humoral antibodies, called enhancing antibodies (blocking antibodies), may actually favor rather than (blocking antibodies), may actually favor rather than inhibit tumor growth. The mechanisms and relative inhibit tumor growth. The mechanisms and relative importance of such immunologic enhancement are not well importance of such immunologic enhancement are not well

understoodunderstood..

Although many tumors are eliminated by the immune system (and thus are never detected), others continue to grow despite the presence of TAAs. Several mechanisms have been proposed to explain this deficient host response to the TAA

Although many tumors are eliminated by the immune system (and thus are never detected), others continue to grow despite the presence of TAAs. Several mechanisms have been proposed to explain this deficient host response to the TAA

How does a tumor escape immune surveillance?How does a tumor escape immune surveillance?

Generation of regulatory cells (CD4Generation of regulatory cells (CD4+CD25CD25+ FoxP3FoxP3+ T cells) T cells)

Secrete immunosuppressive molecules Secrete immunosuppressive molecules

Ex: prostaglandins, transforming growth factor Ex: prostaglandins, transforming growth factor beta (TGF-beta (TGF-), interleukin-10 (IL-10), etc.), interleukin-10 (IL-10), etc.

Tumor

T regs

M

CTL

IL-10, etc

Failure to process and present tumor Ag.Failure to process and present tumor Ag.

tumor

Macrophage

T helper (Th) cell

B cell

Cytotoxic T lymphocyte (CTL)

tumor Ag tumor

tumor

MHC Class I

MHC Class II

Downregulation of MHC expression on Downregulation of MHC expression on tumor cell (CTL resistant but NK tumor cell (CTL resistant but NK sensitive)sensitive)

NK cellTumor

cell

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 Tumors may fail to express costimulatory

molecules involved in T cell activation.molecules involved in T cell activation.

Tumor escape mechanisms:Tumor escape mechanisms:Fas FasL

TumorCTL

FasFasL

TumorCTL

When tumor cells express Fas Ligand,they can kill Fas+ T cells, thereby escapingimmune destruction.

References:References:

Diefenbach & Raulet, Innate and adaptive tumor Diefenbach & Raulet, Innate and adaptive tumor immunityimmunity

Kuby , Cancer and the Immune System Kuby , Cancer and the Immune System Last full review/revision June 2009 by Dmitry Last full review/revision June 2009 by Dmitry

Gabrilovich, MD, PhD,Host Response to TumorsGabrilovich, MD, PhD,Host Response to Tumors

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