IMMUNE SUEVEILLANCE AND IMMUNOLOGY OF MALIGNANCY

The battle between immune system and cancer!!

CANCER

ACKNOWLEDGEMENTS

GUIDED AND MOTIVATED BY:

Dr. Hema Suryawanshi Dr. Akshay Dhobley Dr.Pramod Sharma Dr. Rolly Gupta

Presented by: Neha Gupta

PG 2nd yr

CONTENTS: Prologue Timeline Cancer immunoediting Studies Cytolytic capacity Patrolling transformation Tumour antigens Equilibrium phase Escape phase Immunotherapy Conclusion References

PROLOGUE

BASIC KNOWLEDGE OF CANCER • What is Cancer?• How does cancer occur?• How many types of cancers?• Current therapeutic strategies for cancers

Definitions of Cancer

Cancer consists of single clones or several clones of cells that are capable of independent growth in the host.

Cancer cells arise from host cells via neoplastic transformation or carcinogenesis.

Physical, chemical and biological agents may cause cancer.

CARCINOGENS

Physical

Chemical

Biological

Hereditary

CARCINOGENESIS

CANCER IMMUNOSURVEILLANCE

INTRODUCTION

The last fifteen years have seen a reemergence of interest in cancer immunosurveillance and a broadening of this concept into one termed cancer immuno- editing. The latter, supported by strong experimental data obtained by studying human cancer, holds that the immune system not only protects the host against development of primary nonviral cancers but also sculpts tumour immunogenecity.

Comments made decades ago by the architects of the cancer immunosurveillance hypothesis, Burnet and Thomas, that “there is little ground for optimism about cancer”(Burnet,1957) and “the greatest trouble with the idea of immunosurveillance is that it cannot be shown to exist in experimental animals” (Thomas, 1982).

With the development of mouse tumor models using inbred mice with molecularly defined immunodefi- ciencies, it has become possible to demonstrate the existence of a cancer immunosurveillance process that can prevent primary tumor growth.

FROM CANCER IMMUNOSURVEILLANCE TO IMMUNOEDITING: TIMELINE

In 1909, Paul Ehrlich predicted that the immune system repressed the growth of carcinomas that he envisaged would otherwise occur with great frequency.

Fifty years later as immunologists gained an enhanced understanding of transplantation and tumor immunobiology and immunogenetics, F. Macfarlane Burnet and Lewis Thomas revisited the topic of natural immune protection against cancer .

Burnet believed that tumor cell-specific neo-antigens could provoke an effective immunologic reaction that would eliminate developing cancers (Burnet,1957,1964,1971).

Thomas theorized that complex long-lived organisms must possess mechanisms to protect against neoplastic disease similar to those mediating homograft rejection (Thomas, 1959).

Old and Boyse, 1964:stated that sentinel thymus dependent cells of the body constantly surveyed host tissues for nascently transformed cells .

Stutman, 1974-1979: new studies fueled by tech nologic advances in mouse genetics and monoclonal antibody (mAb) production—reinvigorated and ulti mately validated the cancer immunosurveillance concept.

Smyth et al., 2001b; Dunn et al., 2002, 2004 expanded it to incorporate the contributions of both innate and adaptive immunity,

However, there has been a growing recognition that immunosurveillance represents only one dimension of the complex relationship between the immune system and cancer (Dunn et al., 2002, 2004; Schreiber et al., 2004).

Recent work has shown that the immune system may also promote the emergence of primary tumors with reduced immunogenicity that are capable of escaping immune recognition and destruction (Shankaran et al).

These findings prompted the development of the cancer immunoediting hypothesis to more broadly encompass the potential host-protective and tumor-sculpting functions of the immune system throughout tumor development (Dunn et al., 2002, 2004).

CANCER IMMUNOEDITING:PHASESELIMINATION EQULIBRIUM ESCAPE

THE ELIMINATION PHASE 1st phase: antitumour immune response

2nd phase: limited tumour death

3rd phase: apoptosis

4th phase: destruction of remaining antigen bearing tumour cells

ROLE OF INNATE AND ADAPTIVE IMMUNITY Rapid accumulating data have begun to elucidate that

lymphocytes of both the adaptive and innate immune compartments prevent tumour development.

Lymphocytes expressing rearranged antigen receptors play critical roles in the cancer immunosurveillance process.

STUDIES ON KNOCKOUT MICE

RAG-2 -/- mice injected with chemical carcinogen MCA ,the mice developed sarcomas at the injection site faster and with greater frequency than strain matched with wild type controls.

NK and NKT cells also participate in cancer immunosurveillance . Mice depleted of both NK and NKT cells by using the anti NK1 were 2-3 times more prone to MCA induced tumourogenesis.

A recent provocative study by Cui et al. (Cui et al., 2003)provides further evidence that innate immune cells comprise an important arm of the immunosurveillance network.

A single mouse was serendipitously found that failed to form ascites when injected intraperitoneally with the extremely aggressive S180 sarcoma cell line.

Subsequent breeding revealed that the obtained served cancer resistance trait was germline transmisslble and was likely controlled by a single autosomal dominant locus.

These data taken together highlight roles of both innate and adaptive immunity in the elimination phase of cancer immunosurveillance.

Cancer immunosurveillance appears to be a multivariable process in which immunologic responses are influenced by a tumour’s cellular origin,anatomic location,stromal response,cytokine production profile,and inherent immunogenecity.

CYTOLYTIC CAPACITY

The second critical effector function of cancer immunosurveillance is the immune system’s ability to kill tumor cells.

Early studies identified perforin (pfp) as a critical cytolytic molecule in the primary host antitumor response.

Subsequent studies revealed an important role for the TNF-related apoptosis-inducing ligand(TRAIL)and have underscored the importance of cytotoxicity manifest by innate immunity in immunosurveillance.

PATROLLING TRANSFORMATION How cells of the immunosurveillance network

distinguish nascent transformed or established tumor cells from normal cells?

CD4 and CD8T cells recognize tumor antigens in the context of MHC class II and class I proteins, respectively.

TUMOUR ANTIGENS

Tumor antigens are processed and presented to the adaptive immune system as short peptide fragments known as epitopes on major MHC class I and MHC class II molecules. The MHC class I molecules are expressed by nearly all nucleated cells of the body, and normally present peptides that are generated endogenously in the cells. It is imperative that the cancer cell presents some form of immunogenic antigen in order for the CD8+ CTLs to recognize the tumor cell and destroy it.

The CD8+T-cells are the key effectors of antitumor immunity mediated by the adaptive immune system, and they recognize antigenic epitopes presented in the context of MHC class I molecules.

CD4+ Th cells also play an important role in antitumor immunity, as they enhance and amplify the immune response through costimulation and the local production of cytokines

CAN BE SEGGREGATED INTO 5 CATEGORIES

DIFFERENTIATION ANTIGENS

MUTATIONAL ANTIGENS

OVEREXPRESSED ANTIGENS

CANCER-TESTIS ANTIGENS

VIRAL ANTIGENS

MUTATIONAL ANTIGENS

Mutational antigens are derived from ubiquitous proteins that are mutated in tumor cells. Point mutations, chromosomal translocations, deletions, or gene insertions can lead to the generation of unique tumor antigens distinct for each tumor. The mutational antigens are highly tumor-specific, and some may also be involved in the transformation process.

SHARED TUMOUR SPECIFIC ANTIGENS Shared tumor-specific antigens are antigens whose

expression is usually silenced in normal tissues but are activated in tumors of various histological types. Expression of these antigens on normal tissues has only been detected on placental trophoblasts and testicular germ cells that do not express MHC class I molecules.

TISSUE SPECIFIC DIFFERENTIATION ANTIGENS

Differentiation antigens lack the specificity of tumor-specific shared antigens, as they are differentiation markers that are expressed not just by the malignant cells, but also by the normal cells of the same origin as the cancer cells. Tyrosinase, for example is expressed by both normal melanocytes and most melanoma cells.

OVEREXPRESSED ANTIGENS T-cell activation is dependent on a minimum number

of T-cell receptor/peptide/MHC contacts ; therefore, the overexpression of many proteins in cancer cells could lead to the generation of an immune response to these self-proteins.

The high levels of mutant or wild-type p53 expressed in many cancers make it a potential immunotherapy target, and it has been used against colorectal cancer without inducing autoimmunity

VIRAL ANTIGENS

Viral antigens are foreign and are only found on infected cells, thereby making them ideal targets because of their high specificity.

The human papilloma virus (HPV) E6 and E7 proteins interfere with normal cell-cycle regulation and are required for the viral life cycle.

In addition to tumor antigens presented on MHC molecules, transformed cells may over express other molecular signposts that can function as recognition targets in the immunosurveillance process.

Several studies have pointed to the NKG2D-activating receptor, expressed on NK cells, Υδ T cells, and CD8 αβ T cells as one important component that is used by both adaptive and innate immune cells to distinguish cancer cells from normal cells.

IMMUNOLOGIC SCULPTING OF CANCER

Recent Findings have showed that tumours formed in an immunodeficient environment are as a group more immunogenic than tumours that develop in immuno competent hosts.

This concept recognises that even after escaping immunosurveillance a tumour’s immunogenic phenotype is continuously shaped by the immunological forces in its environment.

THE EQUILIBRIUM PHASE

Based on the experimental systems there exists a period of latency extending from the end of elimination phase to the beginning of the escape phase and the emergence of clinically detectable malignant disease.

THE ESCAPE PHASE

ESCAPE MECHANISMS

IMMUNODETECTION Stealth and camouflage:escaping immunodetection In order to escape successfully both arms of the immune

system, cancer cells have evolved a joint strategy of both stealth and camouflage. They have to hide the tumor antigens they express and disguise themselves as something that the body will not reject.

The fetus is an allograft that survives within the maternal

host despite its low expression of allogenic MHC molecules . The same immune evasion strategies utilized by the fetus “camouflage” the cancer cells and enable them to escape the NK cells.

TRICKING THE NK CELLS

In order to escape NK-mediated killing, cancer cells have evolved to establish tolerance using similar mechanisms as those found in fetal–maternal interactions. HLA-G is a nonclassical MHC class I molecule expressed in the placenta and helps to maintain tolerance to the fetus. It is expressed by many cancers like melanoma, renal carcinoma, lung carcinoma, glioblastoma, and ovarian cancer.

IMMUNOMODULATORY MECHANISMS Cancer cells are basically self-cells that are no longer

regulated by normal cellular processes and proliferate without control. These aberrant cells are predisposed to accumulating genetic errors that place them in a better position to adapt to changes in their environment.

Like organisms predicted by Darwin’s Theory of Natural Selection to adapt to the environment or suffer extinction, immune pressure selects for tumor variants that are resistant to immune eradication.

Apart from the immune evasion strategies listed, modulation of the immune response to incapacitate the antitumor response is a powerful evolutionary adaptation of the cancer cells.

Most of the immunomodulatory mechanisms found in tumors are based on normal homeostatic control processes of the immune response set in place to prevent unbridled proliferation of the immune cells, or to maintain tolerance towards self-tissues.

DISRUPTING CELL-CELL INTERACTION The intercellular adhesion molecule (ICAM)-1 is

crucial for the formation of the immunological synapse.

ICAM-1 participates in the cell–cell interaction between the NK cell and the malignant cell.

Transformed cells have been shown to disrupt this cellular interaction by producing the matrix metalloproteinase 9, which results in ICAM-1 shedding and resistance to NK cell killing

REQUIREMENT FOR A SECOND SIGNAL

CD40-PROVIDING A HELPING HAND CD40 has been detected on a variety of human cancer

cells, from various origins such as bladder, ovarian, colorectal, liver, lung, pancreas, prostate, cervical, and breast .

It has been shown that CD40 activation on bladder and human gastric carcinoma cells inhibits apoptosis mediated through Fas using a similar mechanism to the one in the B-cell apoptosis rescue.

In addition, CD40 activation is able to induce an increase in the motility of gastric carcinoma cells, and its expression has been detected in the tumor vasculature of renal and breast carcinoma as well as in Kaposi’s sarcoma , suggesting a potential role of CD40 in the angiogenesis and metastasis of cancer.

TUMOUR MICROENVIRONMENT

IMMUNOSUPPRESSIVE CYTOKINES

TRANSFORMING GROWTH FACTOR TGF-β is commonly overexpressed in many cancers

and has many immunosuppressive effects, including the inhibition of T-cell proliferation and their development into CTLs and Th cells .

TGF-β-overexpressing tumors are particularly aggressive, and have been correlated with a more malignant phenotype.

PRODUCTION OF OTHER GROWTH FACTORS

CELLULAR INFILTRATES IN THE TUMOUR

Allies or enemies??

RESISTANCE TO DEATH EFFECTOR MECHANISMS Tumors have evolved ways to become resistant to

the death effector mechanisms, thereby becoming truly impervious to immune attack.

The perforin/granzyme and Fas/FasL pathways are the two main effector mechanisms by which CTLs and NK cells mediate antitumor immunity

THE PERFORIN/GRANZYME PATHWAY

Fas MEDIATED APOPTOSIS

ANTIAPOPTOTIC MOLECULES Bcl-2 and Bcl-Xl

COUNTERATTACK BY TUMOUR CELLS

ANGIOGENIC PROCESS FACILITATING TUMOUR INVASION

VEGF is a key mediator in both vasculogenesis and angiogenesis .

VEGF expression is associated with poor prognosis and increased metastatic spreading in ovarian cancer. In addition, VEGF also inhibits T-cell development and contributes to tumor-mediated immune suppression

IMMUNOTHERAPY

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REFERENCES Dunn, Lloyd , Schreiber. The Immunobiology Review of Cancer

Immunosurveillance and Immunoediting:Immunity, Vol. 21, 137–148, August, 2004.

Yi Ting Koh, M. Luz García-Hernández, and W. Martin Kast. Tumor Immune Escape Mechanisms. Cancer Drug Discovery and Development: Cancer Drug Resistance Humana Press Inc., Totowa, NJ.

Cotran,kumar,Robbins.Neoplasia,Robbins Pathologic basis of disease.6th ed,Harcourt Asia 94.

Olivera J. Finn. Molecular Origins of Cancer. Cancer Immunology. N Engl J Med 2008;358:2704-15.

Oki K. Dzivenu, D.Phil., and Jill O’Donnell-Tormey.CANCER AND THE IMMUNE SYSTEM: The Vital Connection.The cancer research institute.