The modern view of immunology suggests that the immune system can recognize potential antigens independent of self non-self discrimination if they are presented in association with sufficient co-stimulatory signals as those that occur in special

1 Immunogenetics Section, Department of Transfusion Medicine, Clinical Center, National Institutes of Health, Bethesda, MD, 20892, USA

2 Universita' degli Studi di Milano, Department of Human Morphology, via Mangiagalli 31, 20133 Milan Italy

E. Yefenof (ed.), Innate and Adaptive Immunity in the Tumor Microenvironment. © Springer 2008

pathophysiological conditions such as pathogen infection, autoimmune reactions and presence of allogeneic tissues [1]. Thus, it may be suggested that allograft rejection may not only reflect the presence of non-self antigens on the surface of heterologous cells but other conditions may contribute to immune-mediated rejection. Those conditions may be similar to those necessary for immune-mediated tissue-specific destruction in other circumstances in which self non-self discrimination is not pertinent such as acute flares of auto-immunity when self molecules are target of immune effector cells. Astride between the inevitable allo-recognition of transplanted organs in the absence of immune suppression and the occasional self-recognition when autoimmunity occurs, is the variable response of immune cells to pathogen invasion. In this case, although pathogens represent non-self entities, the response to the immune system may vary broadly from rapid clearance of the offending organism during an acute infectious event to a chronic reaction that perpetuates in some cases for the lifetime of the affected organism as in the case of chronic hepatitis C virus (HCV) infection [2].

The immune response to cancer sits in between the chronic course of unresolving infections and the persistence of mild autoimmune diseases. In particular, some cancer such as melanoma display a natural tendency to elicit recognition of autologous non-mutated tumor antigens [3] and prime systemic immune responses [4] that, however, are most often insufficient to eradicate the disease. Thus, like in the case of HCV infection, recognition of the antigen is not sufficient and a lingering chronic inflammatory status persists indefinitely wedding indefinitely the pathogen with its host. An overview of various types of immune pathologies, suggests that acute inflammation is necessary for destruction of the pathogenic process whether with beneficial (clearance of pathogen, rejection of cancer) or detrimental (allograft rejection, autoimmunity) results [5]. Thus, inflammatory processes are ultimately required to activate immune effector cells within the target tissue. We have recently proposed that, independently of the triggering events associated with different immune pathologies, such acute activation of immune effectors follows a common final pathway to which we referred to as the immunological constant of rejection [5]. If insufficient pro-inflammatory signals are produced by the pathogenic process, a lingering immune response persists that self perpetuates without eliminating the pathogenic stimulus. This is the most frequent occurrence in cancer. As we will discuss later, the literature has increasingly produced extensive information about immunological or broader biological reasons to explain the frequent incompetence of the immune response toward cancer. Here, we will discuss briefly such mechanism but in the end we will try consider those cases in which tumors are rejected in autologous settings in humans to try to understand how immune manipulation seems to overcome regulatory mechanisms physiologically present in all individuals or induced by the cancer-bearing status.

Before addressing the potentials of antitumor immune responses, it is worth addressing the conflicting perception of the role of the immune response (also referred to as inflammation) in cancer. In fact, the role played by the immune-system in modulating cancer growth and/or its rejection remains perplexing and a matter of active debate. Several investigators propose that immune responses that generate a chronic inflammatory status foster cancer growth [5-11]. For instance, chronic viral and bacterial infections may contribute to more than 1 million cases of infection-related malignancies per year [12, 13]. Two among many interesting examples of virally-induced carcinogenesis are Epstein-Barr virus (EBV) latent infections and chronic HCV. While the former may have direct oncogenic properties intrinsic to the complex biology of this DNA virus, HCV induced hepato-cellular carcinoma is most likely and predominantly induced by the continuous destruction and remodeling of liver tissue induced by chronic HCV infection [14, 15]. Latent EBV infection can induce two types of neoplastic processes: in immunosuppressed individuals, EBV induces lymphoproliferative disorders that are effectively eliminated by withdrawal of immune suppression [16]. In addition, complete regression of post-transplant lymphoproliferative disorders can be mediated by adoptive transfer of Human Leukocyte Antigen (HLA)-matched EBV-specific cytotoxic T cells (CTL) [17-19] and prophylactic administration of CTL can prevent their insurgence [20]. This observation suggests that in conditions, in which the latent EBV infection is not associated with a known chronic inflammatory process affecting a specific organ, viruses can promote oncogenesis directly but the neoplastic process is kept in check by a competent immune system through adaptive responses. It is presently unknown what biological characteristic of EBV-infected cells can sustain a competent immune response in non-immune suppressed hosts. This information is of extreme interest because lack of lymphoproliferative disease in immune competent hosts represents a most outstanding human model of anti-cancer immune surveillance.

In contrast, EBV-associated tumors such as Burkitt's lymphoma, Hodgkin's disease and nasopharyngeal cancer occur in immune competent individuals and display a restricted expression of EBV proteins [21] which may explain the reduced effectiveness of adoptively transferred EBV specific CTL [21-23]. Thus, the same virus, acting as a potent oncogene, may induce various types of cancers whose insurgence is predicated upon the immune status of the host. In the latter case, however, it can be postulated that a combination of oncogenic properties of the virus and a chronic inflammatory process induced by the latent infection or other factors affecting the upper airways may be together responsible for the insurgence of the neoplasia. In particular, since there is no evidence that patients with nasopharyngeal carcinoma have dramatically perturbed immune function, it seems that in such cases, the virally-transformed cells may have acquired novel immune-regulatory properties that facilitate their escape from immune recognition as suggested by experimental animal models [24]. Alternatively, these EBV-associated cancers may lack the appropriate co-stimulatory properties displayed by EBV-infected B cells.

To the extreme, HCV-induced hepatocellular carcinoma is probably associated with the remodeling and inflammation that characterizes the progression of this cancer from a liver damaged by chronic inflammation and cirrhosis. In fact, a similar disease arises in livers damaged by other chronic conditions such as alcoholic hepatitis or in association with severe hemochromatosis [25]. Hepatocellular carcinoma stands, therefore, as a salient example of a neoplastic process fostered by chronic inflammation independently of its primary cause. This information clearly suggests that chronic inflammatory processes and the immune cells that mediate them favor cancer growth.

While it is clear that the lingering immune responses associated with chronic inflammation foster the growth of several human cancers [5, 11], it is also apparent that in some favorable circumstances activation of the same immune responses can provoke cancer regression in humans providing evidence that tumors can be recognized and rejected by a properly activated immune system [5]. Treatment of metastatic melanoma is a prototype model of the potential immune responsiveness of human cancers [26-28]. One of the peculiarities of this cancer is that it is naturally immunogenic eliciting autologous immune responses against endogenous, non-mutated self-proteins [29, 30]. In this case, a particularly immunogenic micro-environment may be conducive to the induction of a cancer-specific autoimmune response directed against non-mutated self molecules. Possibly, other solid tumors that lack these immune properties are less likely to respond to immune manipulation [31]. Yet, in either case, in the absence of immune stimulation, tumors incrementally grow irrespectively of their potential immune responsiveness suggesting that additional immune stimulation is necessary to complement the naturally occurring immune responses. It is also not clear whether adaptive immune responses (the immune responses that are acquired throughout life after exposure to a given antigen) of the kind frequently observed in the context of melanoma are causative in promoting cancer rejection in humans or represent an epiphenomenon resulting from the intrinsic immunogenicity of melanoma; renal cell cancer is not as efficient in inducing the kind of antigen-specific immune responses observable in melanoma; yet, this cancer is as likely to regress in response to systemic interleukin-2 administration [32, 33]. In addition, recent experimental evidence suggests that the innate immune response that includes effector mechanisms present in each individual impendent of previous antigen exposure may play a prominent role in cancer rejection [34].

A major contribution to the understanding of the complex relationship between melanoma (as a prototype immune responsive cancer model) and its host was the identification and characterization of tumor antigen-specific CD8+ and CD4+ T cells within melanoma metastases [35]. If these tumor antigen-specific immune cells are consistently produced by the host and they can reach the tumor site, why is the rejection of cancer such a rare event [36]? Obviously the simple presence of antigen-specific T cells in not sufficient to induce rejection as illustrated by experimental models in which immune responses foster rather than hamper cancer growth [7, 13, 37] and evidence in humans that chronic infection of bacterial [38] or viral origin [39-42], or other pro-inflammatory stimuli promote cancer growth [43]. Two categories of reasons may explain why effector immune mechanisms cannot control tumor growth: a systemic insufficiency of the immune response (due to immune tolerance and immune suppression), or an insufficiency within the tumor that may be induced by unfavorable conditions within the tumor microenvironment and may include tumor escape mechanisms [44, 45] or simply lack of sufficient co-stimulatory properties of cancer tissues [46, 5, 31]. In this review, we will focus on the latter hypothesis referring the reader to other manuscripts discussing the role of systemic immune deficiencies in tumor bearing hosts [47, 48]. In particular, we will discuss the possible role that various components of the immune system may play within the tumor micro-environment and how their cross talk with cancer or other by-stander cells may modulate their function.

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