Tumor Microenvironment under the Magnifying Glass A New Challenge to Cancer Immunologists

The theory of immunological surveillance against cancer has been introduced half a century ago by McFarlane Burnet and Lewis Thomas. Despite extensive research to validate and generalize this concept, approaches to intervene in cancer by immunological means has led to more disappointments than successes, more doubts than convictions. Is this concept still valid? If the question addresses the possibility that cancer cells induce protective immunity sufficient to enact tumor rejection, the answer is no. But what about manipulating innate and adaptive, cellular and soluble immune components to fight tumor progression and metastasis? A pessimist's answer would allude to the ample evidence demonstrating that most malignant cells are non-immunogenic and do not become "non-self' targets. The optimist will highlight cases of melanoma and non-Hodgkin's lymphoma that can be managed by active and passive immunotherapy. Realistically, however, one has to admit that approaches to induce specific immunity to cancerous cells may be useful in the treatment of tumors with a well-defined etiological factor (viral or carcinogen), leaving most carcinomas and sarcomas outside the scope of potential targets for adaptive immune attack. Nevertheless, when it comes to innate immune responses and factors, the prospects of harnessing inflammatory and growth restricting cytokines, NK cell death receptors and ligands has not been exploited in full. We may be surprised, after all, by research endeavors focusing on these immune components in the future.

In recent years, the study of cancer immunology has been benefited by the emerging concept of the tumor microenvironment.

It is not in heaven .. .neither it is beyond the sea. „.It is very nigh unto thee that you mayest do it. (Deuteronomy 30:11)

The message is clear and straight forward. To discern immune responses pertinent to tumor regression (or progression), one should look nigh to the tumor. Studying of systemic immunity in cancer patients or experimental animals is not always relevant to the antitumor effects operating at the tumor site. Both innate and adaptive immune responses taking place within the tumor and its immediate vicinity are unique and their study should yield novel insights into the role that immunity may play in protecting the host against an emerging or expanding tumor.

In the present issue we undertook the challenge to review and discuss recent studies focusing on the uniqueness of loco-regional anti-(or pro) cancer immunity, manifested at the tumor microenvironment. In Chapter 1, Whiteside reviews evidence suggesting that components necessary for mounting an antitumor immune response are present in cancer patients. Yet, such responses fail to arrest tumor growth due to a loco-regional immune dysfunction within and around the tumor. Multiple mechanisms are involved in creating an immunosuppressive microenvironment at the tumor site, which call for the development of therapies aimed to avoid tumor induced suppression and sustain the function of immune effector cells.

Mechanisms leading to immunosuppression at the tumor microenvironment are discussed in Chapter 2 by Ferrone. It appears that immunosuppressive cytokines such as IL10 and TGF-0 are abundantly produced by tumor, stromal and immune cells at the microenvironment. In addition to their inhibitory effect, such cytokines act directly on cancerous cells by impairing their antigen presenting capacity. Another inhibitory activity is mediated by soluble HLA molecules generated at the tumor microenvironment that induce apoptosis of infiltrating CTL and NK cells with residual cytotoxic activity.

In Chapter 3, Schirrmacher describes and discusses malignant diseases in which tumor growth occurs despite the existence of functional tumor specific memory T cells in the bone marrow. This apparent paradoxical situation reflects the disparity between peripheral and loco-regional immune responses during the progression of cancer. The unique loco-regional characteristics of host tumor relationship require novel intervention modalities which counteract immune and metabolic deregulation in the tumor microenvironment.

Modern technologies enabling gene expression profiling can be applied in the study of cancer microenvironmental immunity. This approach is discussed by Gajewski in Chapter 4 using melanoma microenvironment as a model. An oligonu-cleotide array platform preformed on melanoma biopsies and cell lines identified numerous genes that are upregulated in tumor versus stromal cells. Many such gene transcripts are involved in regulating T and B cell immunity and in crating immunosuppressive microenvironment. Such throughput analysis may help in discerning new targets for manipulating the tumor microenvironment in favor of immunoreactivity.

How can tumors manipulate their microenvironment to escape immune regulation and attack? Multiple mechanisms exist, one of which involves tumor-associated antigens (TAA). Such antigens, as discussed by Engelmann and Finn in Chapter 5, play a Dr. Jekyll and Mr. Hyde game. While in experimental systems and some clinical circumstances they can be targeted by immune surveillance, at the tumor microenvironment they promote tumorigenesis by acting as adhesion or signaling molecules. The Mr. Hyde type of action becomes even more deleterious when TAA are expressed on cancer stem cells, by virtue of their capacity to prevent apoptosis, increase proliferation and induce chemotaxis of immune cells.

Under most circumstances, cancer cells shape their microenvironment in their favor. However, at the same time they are affected by microenvironmental factors that confer upon them heightened status of immunoresistant phenotype. This outcome is discussed by Bonavida in Chapter 6. While immuno-competent cytotoxic lymphocytes infiltrate the growing tumor, they fail to kill tumor cells, since the latter develops a high degree of apoptotic resistance. Both extrinsic and intrinsic mechanisms generated inside and outside the tumor contribute to the gradual acquisition of a resistant phenotype and their identification is required in order to re-sensitize the cells for cytotoxicity.

The cancer microenvironment may be envisaged as a site of chronic inflammation. This view is presented by Selleri et al. in Chapter 7. Evidence has been generated in recent years to indicate that the evolution and progression of certain cancers is promoted by a chronic inflammatory response to viral or bacterial infection. Hence, cellular and soluble components of inflammation at the tumor microenvironment are likely to create a niche favoring tumor growth. Immune modulation and suppression is one outcome of chronic inflammation, manifested in situ, at close proximity to the growing tumor.

The most important effector cells which are directly engaged in tumor cell destruction are Cytotoxic T lymphocytes (CTLs) and natural killer (NK) cells. In Chapter 8, Lotem et al. discuss the events taking place during CTL activation, migration, target recognition, immune synapse formation and killing. While all these steps occur and advance during viral infection or graft rejection, they fail to operate within the tumor microenvironment. This deficiency may be restored using gene transfer technologies by which CTLs are equipped with high affinity T cell receptors (TCR) or TCR replacing molecules, such as chimeric monoclonal antibodies. These manipulations, together with ex vivo expansion and selection of highly reactive CTLs should boost the destructive capacity of the cells, beyond the limiting threshold of the immunosuppressive tumor microenvironment.

Whereas CTLs are a cellular component of the specific/adaptive immune system, NK cells belong to the innate arm of the immune response. As reviewed by Gazit et al. in Chapter 9, the potency of tumor cell killing by NK cells has been demonstrated in various experimental systems. Yet, tumor rejection by NK cell killing is not evident due to microenvironmental factors that inhibit NK activity. Since NK cells are equipped with an array of inhibitory receptors (NKIRs) that interact with MHC and non-MHC ligands, their killing activity at the tumor microenvironment may be inhibited by direct or indirect engagement of such receptors. In addition the immunosuppressive microenvironment of the tumor disarms NK cells by inducing multiple phenotypic changes which should be studied in detail before modalities for harnessing of NK cells to fight cancer are developed.

Conceptually and traditionally, the tumor microenvironment is envisaged as a consequence of malignant transformation in that a growing tumor creates a shield that protects its cells from destruction by immune and non-immune mechanisms. Klein et al. in Chapter 10 provide a different look at the tumor microenvironment. In certain hemopoietic cancers it may play a causative role and promote malignant transformation. This is the case in Hodgkin's and nasal NK/T lymphomas which emerge following infection by EBV. The transforming capacity of this virus is usually offset by robust immunity in the host, leading to persistent latent infection. However, when a certain pattern of viral protein expression ensues, a complex interactive microenvironment comes to exist with unique composition of cellular and soluble components. Such microenvironmental factors promote, rather than inhibit, cellular transformation and tumor progression, and are responsible for the formation of the Hodgkin's lymphoma Granuloma.

This publication is first in a series of Springer Science books dealing with various aspects of the tumor microenvironment. To the best of my knowledge it is a first compilation of chapters discussing the interrelationship between the immune response, the tumor and its microenvironment. Evidently, a focus on the tumor microenvironment provides new and exciting insight into the complex interaction between innate and adaptive, cellular and humoral immune responses and cancer cells. It is a young and evolving concept doing its first steps on a long path of scientific inquiry. The ultimate goal is to design local and systemic immune strategies that will affect the tumor and its environment in a therapeutic manner. Hopefully, the ongoing investment in studying cancer microenvironment will ripe to yield practical dividends in the near future.

Eitan Yefenof

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