Kfc Micro Environment

Cancer is a result of multiple genetic mutations that present the immune system with numerous new antigens, either products of the mutated genes or normal proteins that are aberrantly expressed due to oncogenic mutations. There are many examples of molecules expressed in tumors that are also expressed in normal cells, however on

Department of Immunology, University of Pittsburgh School of Medicine, Pittsburgh, PA 15232, USA

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

tumors they are found either at a much higher concentration, in the wrong location (in the cytoplasm instead of the nucleus, on the entire cell surface instead of polarized), or in a differentially processed form (e.g. tumor-specific glycosylation, phosphorylation, lipidation, etc.). These molecules are collectively known as tumor associated antigens (TAA). This distinguishes them from tumor specific antigens present on cancer cells but not detectable on the normal cell counterparts. They are products of DNA-mutations that cause altered protein structures and often influence their function. In the last two decades, research in the mechanisms of immune recognition of tumors centred in great part on the molecular characterization of tumor antigens and revealed that a large number of these molecules can be recognized by the immune system. However, while this work provided proof that tumors are highly antigenic, it also showed that in spite of often simultaneous expression of multiple antigens on tumors, the immune responses generated against them are weak and do not result in tumor rejection. In the case of TAA that closely resemble self-molecules, weak immune responses are considered to be due to self-tolerance. Indeed, experiments in animal models have shown that immunization against tumor-associated antigens generates much stronger immune responses in wild type mice compared to mice transgenic for these antigens [1-4]. Nevertheless, even in transgenic mice that show evidence of tolerance against these antigens, it is possible to induce immunity strong enough to reject a tumor challenge. There is also accumulating evidence that in people, immune responses that are generated against self-tumor associated antigens may be protective against tumor occurrence [5-8]. Furthermore, the presence of immune responses against several of these antigens in cancer patients is positively correlated with better prognosis.

Many different techniques have been utilized to identify tumor antigens: transfection of recombinant tumor cDNA libraries and human leukocyte antigen (HLA) molecules into target cells [9, 10], isolation of peptides from the binding cleft of major histocompatibility complex (MHC) class I molecules expressed on tumor cells [11, 12], deduction of immunogenic peptide sequences from suspected tumor antigens (such as known oncogenes, tumor suppressor genes or other tumor-associated proteins using computer algorithms based on HLA-anchor motifs) [13, 14], and serological expression cloning of recombinant tumor cDNA expression libraries (SEREX) [15, 16]. They have led to the identification of a large number of molecules that are clearly recognized by the immune system and by that definition are targets of immune surveillance. The question that is of special interest to tumor immunologists is why the immune response against these molecules is not sufficient to prevent tumor outgrowth. It is clearly possible, although difficult to demonstrate, that in most individuals responses against tumor antigens are protective, and some evidence for this is beginning to accumulate [5, 17]. Cancer may only win when it succeeds to escape immune surveillance and this can happen through the loss of specific antigens or gain of immunosuppressive properties.

In parallel to the work on tumor antigen discovery, work has been done on the reasons why tumor antigen-specific immunity fails to control disease. This has proven to be a very rich area for discovery. Numerous immunosuppressive mechanisms have been unveiled and described that are unique to a tumor microenvironment. Tumor microenvironment is an altered local environment in which the incipient neoplasia develops, progresses, and begins to metastasize. Fibroblasts, epithelial cells, adipocytes, smooth muscle cells, inflammatory cells, as well as resident and recruited immune and vascular cells, constitute the stroma that communicates with tumor cells and co-evolves with them over time. In addition, extracellular matrix molecules dynamically interact with tumor cells to provide nutrients and stimuli necessary for tumor proliferation, angiogenesis, invasion and insulation from the host's immunosurveillance. Interaction of cancer cells with their microenvironment is mediated through many cell surface molecules, some of which have been also defined by the immune system as tumor antigens.

In this chapter we will focus on immunosuppressive mechanisms that are promoted by the expression of some well-known tumor antigens that appear to play a dual role reminiscent of the Dr. Jekyll and Mr. Hyde story. Under certain circumstances they can activate effective immunity and serve as good targets for tumor rejection, thus behaving like the good Dr. Jekyll. Unexpectedly and only recently appreciated, these same molecules can contribute to the creation of an immuno-suppressive microenvironment such that immune effector cells that recognize these same antigens, and potentially many other tumor antigens, are prevented from destroying the tumor. That is their bad Mr. Hyde behavior. The success of immu-notherapy based on these antigens will depend on the ability to take advantage of their Dr. Jekyll side and prevent them from showing their Mr. Hyde side.

As a cardinal example of a Dr. Jekyll and Mr. Hyde antigen, we will present in detail the tumor antigen MUC1, which has been extensively studied as a tumor antigen on over 80% of all human solid tumors, as well as multiple myelomas and some B cell lymphomas. It was realized only recently that MUC1 could also be used by the tumor for survival and immune evasion, if it is not targeted efficiently by the immune system for tumor destruction. We will describe also recent realization that MUC1 is expressed on cancer stem cells, where it can be a target for therapy but also a facilitator of their development into mature tumor cells. While much less is known about such dual behavior of other molecules studied as tumor antigens, we will review evidence that at least some of them, such as CEA, tumor glycolipids and gp100, share this dual behavior with MUC1.

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  • Selina
    7 years ago

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