Cancer immunology

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]

## Contents

* 1 Overview
* 2 Immunosurveillance
* 3 Immunoediting
* 3.1 Elimination: Phase 1
* 3.2 Elimination: Phase 2
* 3.3 Elimination: Phase 3
* 3.4 Elimination: Phase 4
* 3.5 Equilibrium and Escape
* 4 Cancer Immunology and Chemotherapy
* 5 The role of viruses in cancer development
* 6 References

## Overview

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Cancer immunology is the study of interactions between the immune system and cancer cells (also called tumors or malignancies). It is also a growing field of research that aims to discover innovative cancer immunotherapies to treat and retard progression of this disease. The immune response, including the recognition of cancer-specific antigens is of particular interest in this field as knowledge gained drives the development of new vaccines and antibody therapies. For instance in 2007, Ohtani published a paper finding tumour infiltrating lymphocytes to be quite significant in human colorectal cancer [1]. The host was given a better chance at survival if the cancer tissue showed infiltration of inflammatory cells, in particular lymphocytic reactions. The results yielded suggest some extent of anti-tumour immunity is present in colorectal cancers in humans.

Over the past 10 years there has been notable progress and an accumulation of scientific evidence for the concept of cancer immunosurveillance and immunoediting based on (i) protection against development of spontaneous and chemically-induced tumors in animal systems and (ii) identification of targets for immune recognition of human cancer [2].

## Immunosurveillance

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Cancer immunosurveillance is a theory formulated in 1957 by Burnet and Thomas, who proposed that lymphocytes act as sentinels in recognising and eliminating continuously arising, nascent transformed cells [2, 3]. Cancer immunosurveillance appears to be an important host protection process that inhibits carcinogenesis and maintains regular cellular homeostasis [4]. It has also been suggested that immunosurveillance primarily functions as a component of a more general process of cancer immunoediting [2].

## Immunoediting

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Immunoediting is a process by which a person is protected from cancer growth and the development of tumour immunogenicity by their immune system. It is comprised of three main phases: elimination, equilibrium and escape [5] . The elimination phase consists of the following four phases:

### Elimination: Phase 1

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The first phase of elimination involves the initiation of antitumor immune response. Cells of the innate immune system recognise the presence of a growing tumor which has undergone stromal remodeling, causing local tissue damage. This is followed by the induction of inflammatory signals which is essential for recruiting cells of the innate immune system (eg. natural killer cells, natural killer T cells, macrophages and dendritic cells) to the tumor site. During this phase, the infiltrating lymphocytes such as the natural killer cells and natural killer T cells are stimulated to produce IFN-gamma.

### Elimination: Phase 2

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In the second phase of elimination, newly synthesised IFN-gamma induces tumor death (to a limited amount) as well as promoting the production of chemokines CXCL10, CXCL9 and CXCL11. These chemokines play an important role in promoting tumor death by blocking the formation of new blood vessels. Tumor cell debris produced as a result of tumor death is then ingested by dendritic cells, followed by the migration of these dendritic cells to the draining lymph nodes. The recruitment of more immune cells also occurs and is mediated by the chemokines produced during the inflammatory process.

### Elimination: Phase 3

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In the third phase, natural killer cells and macrophages transactivate one another via the reciprocal production of IFN-gamma and IL-12. This again promotes more tumor killing by these cells via apoptosis and the production of reactive oxygen and nitrogen intermediates. In the draining lymph nodes, tumor-specific dendritic cells trigger the differentiation of Th1 cells which in turn facilitates the development of CD8+ T cells.

### Elimination: Phase 4

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In the final phase of elimination, tumor-specific CD4+ and CD8+ T cells come to the tumor site and the cytolytic T lymphocytes then destroy the antigen-bearing tumor cells which remain at the site.

### Equilibrium and Escape

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Tumor cell variants which have survived the elimination phase enter the equilibrium phase. In this phase, lymphocytes and IFN-gamma exert a selection pressure on tumor cells which are genetically unstable and rapidly mutating. Tumor cell variants which have acquired resistance to elimination then enter the escape phase. In this phase, tumor cells continue to grow and expand in an uncontrolled manner and may eventually lead to malignancies. In the study of cancer immunoeditting, knockout mice have been used for experimentation since human testing is not possible [2]. Tumor infiltration by lymphocytes is seen as a reflection of a tumor-related immune response [6].

## Cancer Immunology and Chemotherapy

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Obeid et al.[11] investigate how inducing immunogenic cancer cell death ought to become a priority of anticancer chemotherapy for the reason that, the immune system would be able to play a factor via a ‘bystander effect’ in eradicating chemotherapy-resistant cancer cells [12-14]. However, extensive research is still needed on how the immune response is triggered against dying tumour cells [15].

Professionals in the field have hypothesized that ‘apoptotic cell death is poorly immunogenic whereas necrotic cell death is truly immunogenic’ [16-18]. This is perhaps because cancer cells being eradicated via a necrotic cell death pathway reduce an immune response by triggering dendritic cells to mature, due to inflammatory response stimulation [19-20]. On the other hand, apoptosis is connected to slight alterations within the plasma membrane causing the dying cells to be attractive to phagocytic cells [21].

Thus Obeid et al. [11] propose that the way in which cancer cells die during chemotherapy is vital. Anthracyclins produce a beneficial immunogenic environment. The researchers report that when killing cancer cells with this agent uptake and presentation by antigen presenting dendritic cells is encouraged, thus allowing a T-cell response which can shrink tumours . Therefore activating tumour-killing T cells is crucial for immunotherapy success [22].

However, advanced cancer patients with immunosuppression have left researchers in a dilemma as to how to activate their T cells. The way the host dendritic cells react and uptake tumour antigens to present to CD4+ and CD8+ T cellsis the key to success of the treatment [22].

## The role of viruses in cancer development

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Various strains of Human Papilloma Virus (HPV) have recently been found to play an important role in the development of Cervical Cancer. The HPV oncogenes E6 and E7 that these viruses possess have been shown to immortalise some human cells and thus promote cancer development [7]. Although these strains of HPV have not been found in all cervical cancers, they have been found to be the cause in roughly 70% of cases. The study of these viruses and their role in the development of various cancers is still continuing, however a vaccine has been developed that can prevent infection of certain HPV strains, and thus prevent those HPV strains from causing cervical cancer, and possibly other cancers as well.

A virus that has been shown to cause breast cancer in mice is Mouse Mammary Tumour Virus (MMTV) [8, 9]. It is from discoveries such as this and the role of HPV in cervical cancer development that research is currently being undertaken to discover whether or not Human Mammary Tumour Virus is a cause of breast cancer in humans [10].

## References

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1\. Ohtani, H. (2007) 'Focus on TILs: Prognostic significance of tumor infiltrating lymphocytes in human colorectal cancer', Cancer Immunity. 7: 4.

2\. Dunn, G. P, Bruce, A. T, Ikeda, H., Old, L. J. & Schreiber, R. D. (2002) 'Cancer immunoediting: from immunosurveillance to tumor escape', Nature Immunology. 3(11):. 991-998.

3\. Burnet, F.M. (1957) 'Cancer—a biological approach', Brit. Med. J. 1:841−847.

4\. Kim, R., Emi, M. & Tanabe, K. (2007) 'Cancer immunoediting from immune surveillance to immune escape', Journal of Immunology. 121(1):1-14.

5\. Dunn, G. P., Old, L. J. & Schreiber, R. D. (2004) 'The Three Es of Cancer Immunoediting', Annual Review of Immunology. 22:329-360.

6\. Odunsi, K. & Old, L. (2007) 'Tumor infiltrating lymphocytes: indicators of tumor-related immune responses', Cancer Immunity. 7:3.

7\. Hausen. H. (2000). Papillomaviruses Causing Cancer: Evasion for Host-Cell Control in Early Events in Carcinogenesis. Journal of the National Cancer Institute. 92(9):690-698.

8\. Brittner. J. J. (1943) Possible relationship of the oestrogenic hormones, genetic susceptibility and milk influence in the production of mammary cancer in mice. Cancer Research, 2: 710-721

9\. Callahan R., Smith. G. H. (2000). MMTV-induced mammary tumorigenesis: gene discovery, progression to malignancy and cellular pathways. Oncogene, 19: 992-1001.

10\. Glenn W. K., Whitaker. N. J., Lawson. J. S. (2006). Presence of mouse mammary tumour-like virus (MMTV) gene sequences may be associated with specific breast cancer morphology. J Clin Pathol. 60(9):1071

11\. Obeid, M., Tesniere, A., Ghiringhello, F., Fimia, G.M., Apetoh, L., Perfettini, J.L., Castedo, M., Mignot, G., Panaretakis, T., Casares, N., Metivier, D., Larochette, N., van Endert, P., Ciccosanti, F., Piacentini, M., Zitvogel, L., Kroemer, G. (2007) Calreticulin exposure dictates the immunogenicity of cancer cell death. Nature Medicine. 13(10) :54-61.

12\. Steinman, R.M. & Mellman, I. (2004). Immunotherapy bewitched, bothered, and bewildered no more. Science 305:197–200.

13\. Lake, R.A. & van der Most, R.G. (2006). A better way for a cancer cell to die. N. Engl. J. Med. 354:2503–2504.

14\. Zitvogel, L., Tesniere, A. & Kroemer, G. (2006) Cancer in spite of immunosurveillance: immunoselection and immunosubversion. Nat. Rev. Immunol. 6:715–727.

15\. Zitvogel, L., Casares, N., Pequignot, M., Albert, M.L. & Kroemer, G. (2004). The immune response against dying tumor cells. Adv. Immunol. 84:131–179.

16\. Bellamy, C.O., Malcomson, R.D., Harrison, D.J. & Wyllie, A.H. (1995). Cell death in health and disease: the biology and regulation of apoptosis. Semin. Cancer Biol. 6:3–16

17\. Thompson, C.B. (1995) Apoptosis in the pathogenesis and treatment of disease. Science 267:1456–1462

18\. Igney, F.H. & Krammer, P.H. (2002). Death and anti-death: tumour resistance to apoptosis. Nat. Rev. Cancer 2:277–288.

19\. Steinman, R.M., Turley, S., Mellman, I. & Inaba, K. (2000). The induction of tolerance by dendritic cells that have captured apoptotic cells. J. Exp. Med. 191:411–416

20\. Liu, K., Iyoda, T., Saternus, M., Kimura, Y., Inaba, K., Steinman, R.M. (2002). Immune tolerance after delivery of dying cells to dendritic cells in situ. J. Exp. Med. 196:1091–1097

21\. Kroemer, G., El-Deiry, W.S., Goldstein, P., Peter, M.E., Vaux, D., Vandenabeele, P., Zhivotovsky, B., Blagosklonny, M.V., Malorni, W., Knight, R.A., Piacentini, M., Nagata, S., Melino, G. (2005). Classification of cell death: recommendations of the Nomenclature Committee on Cell Death. Cell Death Differ. 12:1463–1467.

22\. Storkus WJ & Falo Jr LD. (2007). A ‘good death’ for tumor immunology. Natue Medicine 13(1):28-30.

23\. Gavin P. Dunn, Catherine M. Koebel and Robert D. Schreiber. (2006). Interferons, immunity and cancer immunoediting. NATURE REVIEWS IMMUNOLOGY 6 (11): 836-848

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