Cancer Immunosurveillance and Immunoediting: The Roles of Immunity in Suppressing Tumor Development and Shaping Tumor Immunogenicity

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Abstract

Cellular transformation and tumor development result from an accumulation of mutational and epigenetic changes that alter normal cell growth and survival pathways. For the last 100 years, there has been a vigorous debate as to whether the unmanipulated immune system can detect and eliminate such altered host derived cells despite the fact that cancer cells frequently express either abnormal proteins or abnormal levels of normal cellular proteins that function as tumor antigens. In this review, we discuss the current state of this argument and point out some of the recent key experiments demonstrating that immunity not only protects the host from cancer development (i.e., provides a cancer immunosurveillance function) but also can promote tumor growth, sometimes by generating more aggressive tumors. The terminology “cancer immunoediting” has been used to describe this dual host protective and tumor promoting action of immunity, and herein we summarize the ever‐increasing experimental and clinical data that support the validity of this concept.

Introduction

After a century of controversy, the notion that the immune system regulates cancer development is experiencing a new resurgence. For the last five decades much of the debate centered on the validity of the cancer immunosurveillance hypothesis originally proposed by Burnet and Thomas (Burnet 1957, Thomas 1959) and reflected the inherent difficulties of experimentally revealing whether natural immune defense mechanisms could protect the host against the development of cancers of nonviral origin. Recently, however, an overwhelming amount of definitive experimental data from mouse models together with compelling clinical data from human patients have demonstrated that a cancer immunosurveillance process that functions as an effective extrinsic tumor suppressor mechanism indeed exists. At the same time there has been a growing recognition that tumor elimination represents only one dimension of the complex relationship between the immune system and cancer (Dunn 2002, Dunn 2004a, Dunn 2004b, Schreiber 2004, Shankaran 2001). When the immune system fails to eliminate all tumor cells, tumors with reduced immunogenicity may emerge that are capable of escaping immune recognition and destruction (Shankaran 2001, Smyth 2000a, Svane 1996, Takeda 2002). This combination of host‐protective and tumor‐promoting functions of the immune system throughout tumor development has been termed “cancer immunoediting” (Dunn 2002, Dunn 2004a, Dunn 2004b, Shankaran 2001) and has been envisaged as a dynamic process composed of three phases: elimination, equilibrium, and escape. Elimination embodies the classical concept of cancer immunosurveillance, equilibrium is the period of immune‐mediated latency after incomplete tumor destruction, and escape refers to the final outgrowth of tumors that have outstripped immunological restraints of the equilibrium phase. This review represents an extension of our previous review articles (Dunn 2002, Dunn 2004a, Dunn 2004b, Smyth 2001c) and not only reflects a convergence of thinking by our two laboratories about the process of cancer immunoediting but also our collective optimism that an enhanced understanding of naturally occurring immune system/tumor interactions will lead to the development of more effective immunologically based cancer therapies.

Section snippets

“Intrinsic” Versus “Extrinsic” Tumor Suppressors

Cancers arise by an evolutionary process during which somatic cells mutate and escape the restraints that normally rein in their untoward expansion. Suppressing the emergence of such dysregulated autonomously growing cells is an evolutionary necessity of metazoans, particularly in large, long‐lived organisms where cells in regenerative tissues retain the potential for neoplastic chaos throughout life. Consequently, multiple cellular mechanisms have arisen to forestall uncontrolled cell division

The Cancer Immunosurveillance Hypothesis: Controversy to Resolution

The notion that the immune system protected the host from neoplastic disease was first proposed by Paul Ehrlich (1909). Interestingly, at a similar point in time (1891), William B. Coley made the amazing observation that some cancer patients who developed bacterial infections also experienced tumor regression. Coley subsequently injected cultures of heat‐inactivated bacteria or spent bacterial culture supernatants into cancer patients with advanced disease, and some patients experienced marked

Synopsis of the Tumor Elimination Phase of Cancer Immunoediting

The elimination phase encompasses the original concept of cancer immunosurveillance since it represents the most complete form of the immunoediting process without progression to the two subsequent phases. As an extrinsic tumor suppressor, we envisage that the immune system manifests its effects only after transformed cells have circumvented their intrinsic tumor‐suppressor mechanisms (Macleod, 2000). However, in reality, triggers such as infection with potentially oncogenic viruses may

Immunoediting: When Tumor Cells Survive

Even when the elimination/immunosurveillance phase of cancer immunoediting fails, the relationship between immunity and cancer is far from over. An appreciation of the complexity of the immune system/tumor interaction is based on work that compared the immunogenicities of tumors derived from immunocompromised versus immunocompetent mice. MCA‐induced sarcomas formed in an immunodeficient environment (RAG−/−, SCID, nude, or NKT cell‐deficient mice) are, as a group, more immunogenic than tumors

Cancer Immunosurveillance/Immunoediting in Humans

Clearly, immunodeficient humans have a far greater susceptibility to lethal viruses and pathogens than immune compromised mice in pathogen free mouse animal facilities, and therefore the opportunities of observing increased spontaneous tumor formation in people with mutations in specific genes encoding immune effector molecules are rare. Studies in broadly immunodeficient patients have documented a highly elevated incidence of virus‐induced malignancies such as non‐Hodgkin's lymphoma, Kaposi's

Conclusions

In this review, we have summarized the strong evidence that now supports the existence of an effective cancer immunosurveillance process that prevents cancer development in both mice and humans. We have discussed the various leukocyte subsets, effector molecules, and methods of tumor recognition that contribute to natural host immune suppression of tumors. Moreover, we have presented the rationale for refining the cancer immunosurveillance hypothesis into one that we have termed cancer

Acknowledgments

This review is dedicated to Dr. Lloyd J. Old on the occasion of his retirement as Scientific Director of the Ludwig Institute for Cancer Research. Lloyd Old has been a constant source of inspiration, information, encouragement and support to the field of tumor immunology in general and to the authors of this review in particular. The authors also wish to acknowledge the particularly helpful contributions of science and discussion that Dr. Yoshohiro Hayakawa made to this review. We are grateful

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