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• W192003713 abstract "The goal of this review is to summarize where the field of tumor immunology is today and to emphasize the intimate, two-way interactions that exist between tumor immunology and basic immunology. Tumor immunology lies at the intersection of two large, complex, and somewhat inbred disciplines: cancer research and immunology. It is perhaps best thought of as two fields: the use of cancer as a model system in which to test immunologic principles, and the use of immunology as a tool to understand and treat cancer. The ultimate measure of immunological progress is how well basic concepts can be integrated, synthesized, and applied to real problems like cancer, autoimmunity, and infectious diseases. By this measure, immunology remains in its infancy. Much of tumor immunology is intended to probe the limits of current immunologic concepts by experiments in murine cancer models. Success is measured by the extent to which the concepts are tested and refined and not by their impact on human disease, although there is a reductionist bias that this will be the ultimate result. Immunotherapy, especially T cell–directed immunotherapy, dominates the current applications of immunology to the understanding and treatment of cancer. Studies in this field have investigated the role that cells and secreted products of the immune system play in creating an environment either conducive or hostile to malignant transformation, early tumor growth, and angiogenesis. Some immunotherapy efforts are molecularly defined and relate to current immunologic concepts, and others are more empirical. While immunotherapy has yet to experience striking success, some immune-based therapies are already having an impact on cancer treatment. The basic principles that underlie contemporary tumor immunology are simple but have evolved considerably in the past decade: (1) the normal immune system is rarely a significant barrier to tumor growth, although lymphocytes play both positive and negative roles in tumor growth and development; (2) tumors are antigenic; and (3) manipulation of the immune system can lead to complete tumor eradication. The first two are well established, but the third has been proven to date only for a few special cases. Although it is clear that “immunological surveillance” in the strict sense of 8Burnet F.M. The concept of immunological surveillance.Prog. Exp. Tumor Res. 1970; 13: 1-27Crossref PubMed Google Scholar has limited validity (but see below), cells of the immune system play important roles in tumor biology that have nothing to do with specific immunity. As a result, the infiltration of tumors by these cells is not necessarily an indicator of a specific immune reaction, and it cannot be assumed to be a favorable indicator for either the untreated clinical course or the applicability of immunotherapy. Cells of the immune system are sources of growth factors, oxidative products, and regulators of angiogenesis, and they frequently appear to facilitate tumor growth. For example, the aggressive growth of some variants of ultraviolet light (UV)-induced tumors has been shown to require granulocytes (52Pekarek L.A. Starr B.A. Toledano A.Y. Schreiber H. Inhibition of tumor growth by elimination of granulocytes.J. Exp. Med. 1995; 181: 435-440Crossref PubMed Scopus (245) Google Scholar). Mast cells can stimulate cancer growth under some conditions (15Dimitriadou V. Koutsilieris M. Mast cell-tumor cell interactions for or against tumour growth and metastasis?.Anticancer Res. 1997; 17: 1541-1550PubMed Google Scholar). Oxidative products like nitric oxide can serve as mutagens and facilitate tumor growth and metastasis, in addition to killing tumor cells (35Lala P.K. Significance of nitric oxide in carcinogenesis, tumor progression and cancer therapy.Cancer Metastasis Rev. 1998; 17: 1-6Crossref PubMed Scopus (77) Google Scholar). Macrophages play several critical roles in tumor angiogenesis, including conversion of plasminogen to angiostatin (16Dong Z. Kumar R. Yang X. Fidler I.J. Macrophage-derived metalloelastase is responsible for the generation of angiostatin in Lewis lung carcinoma.Cell. 1997; 88: 801-810Abstract Full Text Full Text PDF PubMed Scopus (443) Google Scholar). Immune system enhancement of tumor growth is especially common in hematopoietic tumors, where normal physiologic networks of cytokines and cell surface interactions become driving forces in tumor growth (66Umansky V. Schirrmacher V. Rocha M. New insights into tumor-host interactions in lymphocyte metastasis.J. Mol. Med. 1996; 74: 353-363Crossref PubMed Scopus (29) Google Scholar). Finally, the lymphocyte-specific genomic instability inherent in antibody and T cell receptor (TCR) gene rearrangements is a factor in the majority of lymphoid malignancies (30Kirsch I.R. Lista F. Lymphocyte-specific genomic instability and risk of lymphoid malignancy.Semin. Immunol. 1997; 9: 207-215Crossref PubMed Scopus (21) Google Scholar). All of these aspects of tumor–immune system interaction are understudied and insufficiently acknowledged in tumor immunology studies. However, the normal immune system can also effectively prevent or limit tumor growth in some cases. Immunological surveillance clearly exists for virally derived tumors and nonmelanoma skin cancers (31Klein G. Immunological surveillance against neoplasia.Harvey Lect. 1975; 69: 71-102Google Scholar). Beyond this, immunological surveillance was discounted for many years, but it has recently enjoyed a mild resurgence on the basis of solid data. There is statistical evidence that it can extend to some of the other common solid tumors (6Birkeland S.A. Storm H.H. Lamm L.U. Barlow L. Blohme I. Forsberg B. Eklund B. Fjeldborg O. Friedberg M. Frödin L. et al.Cancer risk after renal transplantation in the nordic countries, 1964–1986.Int. J. Cancer. 1995; 60: 183-189Crossref PubMed Scopus (505) Google Scholar). Recent evidence has been presented for a direct role of interferon gamma (IFNγ) in a form of immune surveillance (29Kaplan D.H. Dighe A.S. Shankaran V. Old L.J. Schreiber R.D. Demonstration of an IFNγ dependent tumor surveillance system in immunocompetent mice.Proc. Natl. Acad. Sci. USA. 1998; 95: 7556-7561Crossref PubMed Scopus (1094) Google Scholar), and TCR Vγ1.1 cells in mice appear to react spontaneously against acute T cell leukemias (53Penninger J.M. Wen T. Timms E. Potter J. Wallace V.A. Matsuyama T. Ferrick D. Sydora B. Kronenberg M. Mak T.W. Spontaneous resistance to acute T-cell leukaemias in TCRVγ1.1Jγ4Cγ4 transgenic mice.Nature. 1995; 375: 241-244Crossref PubMed Scopus (40) Google Scholar). Statistical evidence exists for selection against lung cancers bearing p53 mutations predicted to be strongly antigenic (71Wiedenfeld E.A. Fernandez-Viña M. Berzofsky J.A. Carbone D.P. Evidence for selection against human lung cancers bearing p53 missense mutations which occur within the HLA A*0201 peptide consensus motif.Cancer Res. 1994; 54: 1175-1177PubMed Google Scholar). It is now widely accepted that few spontaneous tumors are immunogenic, but most, if not all, are antigenic. A substantial number of T cell–defined tumor antigens of various types have been isolated from rodent and human tumors (68Van den Eynde B.J. van der Bruggen P. T cell defined tumor antigens.Curr. Opin. Immunol. 1997; 9: 684-693Crossref PubMed Scopus (561) Google Scholar). All of the early studies concentrated on antigens recognized by CD8+ T cells, but work has recently been extended to antigens recognized by CD4+ T cells. In most cases, the T cells used to identify the antigen were tumor-infiltrating lymphocytes (TILs) from a patient or an experimental animal with a progressive tumor. Some of the antigens identified have resulted from tumor-specific mutations, and some are even likely to be related to the transforming event within the tumor cell (72Wölfel T. Hauer M. Schneider J. Serrano M. Wölfel C. Klehmann-Hieb E. De Plaen E. Hankeln T. Meyer zum Büschenfelde K.-H. Beach D. A p16INK4a-insensitive CDK4 mutant targeted by cytolytic T lymphocytes in a human melanoma.Science. 1995; 269: 1281-1284Crossref PubMed Scopus (957) Google Scholar). The surprise so far has been that the majority of the antigens identified in human tumors have been unmutated differentiation antigens inappropriately expressed or overexpressed in the tumor. The era of total genome sequencing is likely to have great influence on future searches for antigenic tumor peptides. The National Cancer Institute has initiated the Cancer Genome Anatomy Project with the goal of characterizing all of the genes expressed in several types of cancer cells (see ). This will ultimately provide the information necessary in a search for potential antigens unbiased by the T cell response in individual patients. The identification of T cell–defined tumor antigens has been critical to the development of the field, but there is no certainty that it has direct application to therapy (7Boon T. Old L.J. Cancer tumor antigens.Curr. Opin. Immunol. 1997; 9: 681-683Crossref PubMed Scopus (254) Google Scholar). The methods used produce little or no evidence that the antigens found can function as tumor-rejection antigens. Moreover, the need to isolate and culture TILs provides the opportunity to introduce artifacts into the system that further reduce the direct relevance of antigen identification (17Faure F. Even J. Kourilsky P. Tumor-specific immune response current in vitro analyses may not reflect the in vivo immune status.Crit. Rev. Immunol. 1998; 18: 77-86Crossref PubMed Google Scholar). Nevertheless, many studies are underway to determine whether antigens identified by these methods can serve as the basis for immunotherapy. Some investigators favor shared antigens because success with a single antigen would be applicable to many patients. The challenge here is to show that shared antigens, which are most commonly unmutated differentiation antigens, can not only be recognized by patient T cells, but can mediate tumor rejection. Others favor unique, mutated antigens because of concerns about tolerance to self-antigens and/or concern about inducing autoimmunity. A challenge here is to demonstrate that unique tumor antigens in humans have not induced peripheral tolerance. There has always been a concern that successful cancer therapy would induce autoimmunity with unacceptable immunopathology, although this has been notably absent in virtually every study designed to look for it (24Hara I. Takechi Y. Houghton A.N. Implicating a role for immune recognition of self in tumor rejection passive immunization against the Brown locus protein.J. Exp. Med. 1995; 182: 1609-1614Crossref PubMed Scopus (167) Google Scholar, 69Vierboom M.P.M. Nijman H.W. Offringa R. van derVoort E.I.H. van Hall T. van der Broek L. Fleuren G.J. Kenemans P. Kast W.M. Melief C.J.M. Tumor eradication by wild-type p53-specific cytotoxic T lymphocytes.J. Exp. Med. 1997; 186: 695-704Crossref PubMed Scopus (189) Google Scholar). Until strikingly positive clinical results are obtained in humans, all tumor antigens remain potential but unproven targets for therapy. Studies in mice have established useful principles of tumor immunotherapy. On the cautionary side, they show that current methods have very limited applicability to large, disseminated, and/or well-established tumors and that the tumor-bearing state is hostile to active immunotherapy (discussed below). On the more positive side, mouse studies show no single obvious, insurmountable barrier to turning the level of antigenicity displayed by tumors into effective immunogenicity. This provides a rational basis for exploring the possibility of cancer immunotherapy. Careful studies have generally shown that even “nonimmunogenic” tumors can stimulate primary cytotoxic T lymphocyte (CTL) responses under carefully controlled conditions (39Liu B. Podack E.R. Allison J.P. Malek T.R. Generation of primary tumor-specific CTL in vitro to immunogenic and poorly immunogenic mouse tumors.J. Immunol. 1996; 156: 1117-1125PubMed Google Scholar). Tumors can be eradicated in mice by passive administration of CTL (69Vierboom M.P.M. Nijman H.W. Offringa R. van derVoort E.I.H. van Hall T. van der Broek L. Fleuren G.J. Kenemans P. Kast W.M. Melief C.J.M. Tumor eradication by wild-type p53-specific cytotoxic T lymphocytes.J. Exp. Med. 1997; 186: 695-704Crossref PubMed Scopus (189) Google Scholar) or antibody (24Hara I. Takechi Y. Houghton A.N. Implicating a role for immune recognition of self in tumor rejection passive immunization against the Brown locus protein.J. Exp. Med. 1995; 182: 1609-1614Crossref PubMed Scopus (167) Google Scholar), even when the target antigens are expressed by normal cells. Individual T cell clones can mediate effective anticancer responses, which indicates that tumor heterogeneity is not a consistently fatal limitation (9Cheever M.A. Chen W. Therapy with T cells principles revisited.Immunol. Rev. 1997; 157: 177-194Crossref PubMed Scopus (75) Google Scholar). Active immunization can be effective, even when expression as a self-antigen limits the response to low-avidity CTL (47Morgan D.J. Kreuwel H.T.C. Fleck S. Levitsky H.I. Pardoll D.M. Sherman L.A. Activation of low avidity CTL specific for a self epitope results in tumor rejection but not autoimmunity.J. Immunol. 1998; 160: 643-651PubMed Google Scholar). Cytokines (and other molecules) transfected into tumor cells can lead to killing of tumors formed by the parental tumor-cell line and can do so through a variety of mechanisms, which are generally more dependent on granulocytes and cytokines than lymphocytes (48Musiani P. Modesti A. Giovarelli M. Cavallo F. Colombo M.P. Lollini P.L. Forni G. Cytokines, tumour-cell death and immunogenicity a question of choice.Immunol. Today. 1997; 18: 32-36Abstract Full Text PDF PubMed Scopus (176) Google Scholar). Immunotherapy has not yet become a force in cancer treatment, but when a broad view is taken of immune-based therapy, the impact has been more significant than is widely appreciated. Some of the impact comes from unexpected areas. For example, monoclonal antibodies (MAbs), given up for dead as therapeutic agents by most immunologists years ago, have staged a quiet comeback. An anti-CD20 MAb has been shown to produce meaningful, if not curative, clinical responses in many B cell lymphoma patients who have failed chemotherapy (40Maloney D.G. Grillo-Lopez A.J. White C.A. Bodkin D. Schilder R.J. Neidhart J.A. Janakiraman N. Foon K.A. Liles T.-M. Dallaire B.K. et al.IDEC-C2B8 (Rituximab) anti-CD20 monoclonal antibody therapy in patients with relapsed low-grade non-Hodgkin’s lymphoma.Blood. 1997; 90: 2188-2195PubMed Google Scholar). The treatment is nontoxic and has been approved by the FDA. Radiolabeled forms of anti-CD20 in development are more toxic but also more active. They have demonstrated potentially curative effects (28Kaminski M.S. Zasadny K.R. Francis I.R. Fenner M.C. Ross C.W. Milik A.W. Estes J. Tuck M. Regan D. Fisher S. et al.Iodine-131-anti-B1 radioimmunotherapy for B-cell lymphoma.J. Clin. Oncol. 1996; 14: 1974-1981Crossref PubMed Scopus (410) Google Scholar, 38Liu S.Y. Press O.W. The potential for immunoconjugates in lymphoma therapy.Hematol. Oncol. Clin. North Am. 1997; 11: 987-1006Abstract Full Text Full Text PDF PubMed Scopus (17) Google Scholar) and may soon be approved for clinical use as well. A 7 year follow-up of MAb 17–1A in Dukes’ stage C colorectal cancer provides convincing evidence for a 32% reduction in mortality in an adjuvant setting (57Riethmüller G. Holz E. Schlimok G. Schmiegel W. Raab R. Höffken K. Gruber R. Funke I. Pichlmaier H. Hirche H. et al.Monoclonal antibody therapy for resected Dukes’ C colorectal cancer seven-year outcome of a multicenter randomized trial.J. Clin. Oncol. 1998; 16: 1788-1794Crossref PubMed Scopus (496) Google Scholar). An antibody to HER2/neu was recently approved by the FDA for use in breast cancer patients. Antibody engineering promises significant improvements in these results. There are several other areas in which immune-based therapy have been effective. In bone marrow transplantation, the graft-versus-leukemia effect is a major factor for diseases like chronic myelogenous leukemia (CML), and its mechanism has been well characterized (5Barrett A.J. Mechanisms of the graft-versus-leukemia reaction.Stem Cells. 1997; 15: 248-258Crossref PubMed Scopus (79) Google Scholar). Donor-lymphocyte transfusions have proved useful to treat relapsed CML and some other hematological malignancies (32Kolb H.-J. Holler E. Adoptive immunotherapy with donor lymphocyte transfusions.Curr. Opin. Oncol. 1997; 9: 139-145Crossref PubMed Scopus (121) Google Scholar). The cytokines interleukin 2 (IL-2) and IFNα-2b have FDA approval for specialized applications, despite severe toxicities. Most antigen-specific vaccine trials are not yet complete but some (e.g., a peptide-based MAGE-3 vaccine) have shown measurable activity (41Marchand M. Weynants P. Rankin E. Arienti F. Belli F. Parmiani G. Cascinelli N. Bourlond A. Vanwijck R. Humblet Y. et al.Tumor regression responses in melanoma patients treated with a peptide encoded by gene MAGE-3.Int. J. Cancer. 1995; 63: 883-885Crossref PubMed Scopus (410) Google Scholar). Vaccination against the idiotype in patients with B cell lymphoma has a significant effect, although the magnitude of the effect and the cost prevent broad application (26Hsu F.J. Caspar C.B. Czerwinski D. Kwak L.W. Liles T.M. Syrengelas A. Taidi-Laskowski B. Levy R. Tumor-specific idiotype vaccines in the treatment of patients with B-cell lymphoma—long-term results of a clinical trial.Blood. 1997; 89: 3129-3135Crossref PubMed Google Scholar). Adoptive T cell therapy has dramatic effects in individual patients. The therapy of choice for some bladder cancers is BCG (55Ratliff T.L. Role of the immune response in BCG for bladder cancer.Eur. Urol. 1992; 21,: 17-21PubMed Google Scholar). These results represent significant progress in cancer treatment, where advances are typically incremental. The realities today in tumor immunology are that tumor cells are normally poor immunogens and that immunotherapy often fails, even when a potent immune response is present. Thus, there are two critical questions that are driving research. First, what properties of the immune system are responsible for the poor immunogenicity, and how can immunogenicity be increased? For this purpose, the fact that the immunogen is a transformed cell is irrelevant. Second, what special properties of cancer cells and the tumor-bearing state present tumor-related barriers to immunotherapy (Figure 1)? To answer the first question, attention is currently focused on antigen presentation. Most tumors are not antigen-presenting cells (APCs), so tumor antigens must normally be routed to professional APCs if they are to stimulate an immune response. While it is possible that some tumor antigens are intrinsically too weak to induce an effective immune response, current evidence suggests that this is not the limiting factor. Antigens known to induce potent immune responses under the appropriate conditions often fail to mediate tumor eradication (62Speiser D.E. Miranda R. Zakarian A. Bachmann M.F. McKall-Faienza K. Odermatt B. Hanahan D. Zinkernagel R.M. Ohashi P.S. Activation of cytotoxic T cells by solid tumours?.J. Exp. Med. 1997; 186: 645-653Crossref PubMed Scopus (276) Google Scholar, 70Wick M. Dubey P. Koeppen H. Siegel C.T. Fields P.E. Chen L. Bluestone J.A. Schreiber H. Antigenic cancer cells grow progressively in immune hosts without evidence for T cell exhaustion or systemic anergy.J. Exp. Med. 1997; 186: 229-238Crossref PubMed Scopus (180) Google Scholar). So what is it about tumor cells that make them such poor vehicles for induction of immune responses? The answer may start with the fact that tumor cells are largely recognized as self. Even many of the antigens on tumor cells that can be recognized by T cells are unmutated differentiation antigens, and foreign antigens expressed on tumor cells sometimes elicit tolerance (64Staveley-O’Carroll K. Sotomayor E. Montgomery J. Borrello I. Hwang L. Fein S. Pardoll D. Levitsky H. Induction of antigen-specific T cell anergy an early event in the course of tumor progression.Proc. Natl. Acad. Sci. USA. 1998; 95: 1178-1183Crossref PubMed Scopus (578) Google Scholar). Thus, some have viewed immunotherapy as an exercise in the controlled induction of autoimmunity (49Nanda N.K. Sercarz E.E. Induction of anti-self-immunity to cure cancer.Cell. 1995; 82: 13-17Abstract Full Text PDF PubMed Scopus (178) Google Scholar, 61Speiser D.E. Ohashi P.S. Self antigens expressed by solid tumors do not efficiently stimulate naive or activated T cells implications for immunotherapy.Cell. Mol. Life Sci. 1998; 54: 263-271Crossref PubMed Scopus (15) Google Scholar). This requires substantial changes in the mode of presentation to the immune system. In the past few years, many attempts to induce immune responses to tumors have involved creation of gene-modified tumor cells that would bypass the need for T cell help or professional APCs, with the hope that the response stimulated would kill both the transfected cells and the untransfected parental tumor. Tumor cells have been transfected with cytokines, initially with the goal of eliminating the need for T cell help or altering the Th1/Th2 cytokine balance (48Musiani P. Modesti A. Giovarelli M. Cavallo F. Colombo M.P. Lollini P.L. Forni G. Cytokines, tumour-cell death and immunogenicity a question of choice.Immunol. Today. 1997; 18: 32-36Abstract Full Text PDF PubMed Scopus (176) Google Scholar, 12Clerici M. Shearer G.M. Clerici E. Cytokine dysregulation in invasive cervical carcinoma and other human neoplasias time to consider the TH1/TH2 paradigm.J. Natl. Cancer Inst. 1998; 90: 261-263Crossref PubMed Scopus (102) Google Scholar). Transfection with costimulatory molecules attempted to make tumor cells into direct antigen-presenting cells (10Chen L. Ashe S. Brady W.A. Hellström I. Hellström K.E. Ledbetter J.A. McGowan P. Linsley P.S. Costimulation of antitumor immunity by the B7 counterreceptor for the T lymphocyte molecules CD28 and CTLA-4.Cell. 1992; 71: 1093-1102Abstract Full Text PDF PubMed Scopus (1062) Google Scholar). While some positive results have been obtained in mice (although rarely with established tumors), careful analysis of the effects observed has returned the focus to professional APCs. Studies showed that even tumor cells expressing high levels of an appropriate class I restricting element and a costimulatory molecule are largely dependent on professional APCs for recognition (27Huang A.Y.C. Bruce A.T. Pardoll D.M. Levitsky H.I. Does B7–1 expression confer antigen-presenting cell capacity to tumors in vivo?.J. Exp. Med. 1996; 183: 769-776Crossref PubMed Scopus (153) Google Scholar), although exceptions exist (3Armstrong T.D. Pulaski B.A. Ostrand-Rosenberg S. Tumor antigen presentation changing the rules.Cancer Immunol. Immunother. 1998; 46: 70-74Crossref PubMed Scopus (43) Google Scholar, 42Maric M. Zheng P. Sarma S. Guo Y. Liu Y. Maturation of cytotoxic T lymphocytes against a B7-transfected nonmetastatic tumor a critical role for costimulation by B7 on both tumor and host antigen-presenting cells.Cancer Res. 1998; 58: 3376-3384PubMed Google Scholar). Intensive efforts are underway to determine whether dendritic cells presenting tumor-derived antigenic peptides can induce an effective antitumor response (58Schuler G. Steinman R.M. Dendritic cells as adjuvants for immune-mediated resistance to tumors.J. Exp. Med. 1997; 186: 1183-1187Crossref PubMed Scopus (405) Google Scholar). The complexities of phenotypic heterogeneity and variations in activation state in dendritic cells will make a thorough investigation of this area a long-term undertaking (4Banchereau J. Steinman R.M. Dendritic cells and the control of immunity.Nature. 1998; 392: 245-252Crossref PubMed Scopus (11835) Google Scholar). Some antigenic tumors appear virtually invisible to the immune system. They induce no response and are not cleared by immune cells introduced by other means (44Melero I. Bach N. Chen L. Costimulation, tolerance and ignorance of cytolytic T lymphocytes in immune responses to tumor antigens.Life Sci. 1997; 60: 2035-2041Crossref PubMed Scopus (41) Google Scholar, 62Speiser D.E. Miranda R. Zakarian A. Bachmann M.F. McKall-Faienza K. Odermatt B. Hanahan D. Zinkernagel R.M. Ohashi P.S. Activation of cytotoxic T cells by solid tumours?.J. Exp. Med. 1997; 186: 645-653Crossref PubMed Scopus (276) Google Scholar, 70Wick M. Dubey P. Koeppen H. Siegel C.T. Fields P.E. Chen L. Bluestone J.A. Schreiber H. Antigenic cancer cells grow progressively in immune hosts without evidence for T cell exhaustion or systemic anergy.J. Exp. Med. 1997; 186: 229-238Crossref PubMed Scopus (180) Google Scholar). This immunological ignorance can often be ameliorated by costimulation, suggesting that antigen presentation is again a key step. Other tumors can induce antigen-specific T cell anergy, and this can be a very early event (64Staveley-O’Carroll K. Sotomayor E. Montgomery J. Borrello I. Hwang L. Fein S. Pardoll D. Levitsky H. Induction of antigen-specific T cell anergy an early event in the course of tumor progression.Proc. Natl. Acad. Sci. USA. 1998; 95: 1178-1183Crossref PubMed Scopus (578) Google Scholar). The simple concept that anergy is induced by encounter with a cell expressing antigen in the absence of costimulation has given way to more complex schemes, in part due to the demonstration that at least some tolerance induction requires professional APCs (1Adler A.J. Marsh D.J. Yochum G.S. Guzzo J.L. Nigam A. Nelson W.G. Pardoll D.M. CD4+ T cell tolerance to parenchymal self-antigens requires presentation by bone marrow-derived antigen-presenting cells.J Exp. Med. 1998; 187: 1555-1564Crossref PubMed Scopus (241) Google Scholar). This further emphasizes the need for a detailed understanding of the interaction of tumor cells with APCs. In view of the finding that fibroblasts can be efficient APCs in lymphoid organs (34Kündig T.M. Bachmann M.F. DiPaolo C. Simard J.J.L. Battegay M. Lother H. Gessner A. Kühlke K. Ohashi P.S. Hengartner H. Zinkernagel R.M. Fibroblasts as efficient antigen-presenting cells in lymphoid organs.Science. 1995; 268: 1343-1347Crossref PubMed Scopus (262) Google Scholar), this understanding must take into account the point of encounter between tumor cells and APCs. Many tumors metastasize to lymph nodes, indicating that localization to lymphoid organs does not in itself confer effective immunogenicity. But there is very little information overall as to whether tumor cells or tumor antigens are present or recognized in lymphoid organs. The danger model of immunity (43Matzinger P. Tolerance, danger, and the extended family.Annu. Rev. Immunol. 1994; 12: 991-1045Crossref PubMed Scopus (3758) Google Scholar) has been referred to often in tumor immunology in recent years, because in its most general sense it summarizes what is often observed in immune responses to tumors (20Fuchs E.J. Matzinger P. Is cancer dangerous to the immune system?.Semin. Immunol. 1996; 8: 271-280Crossref PubMed Scopus (254) Google Scholar, 18Fenton R.G. Longo D.L. Danger versus tolerance paradigms for future studies of tumor-specific cytotoxic T lymphocytes.J. Natl. Cancer Inst. 1997; 89: 272-275Crossref PubMed Scopus (23) Google Scholar). There clearly needs to be some sort of inflammatory milieu to induce effective antitumor immunity. A detailed analysis of the heterogeneous processes induced by cytokine-transfected tumor cells, which can often lead to rejection of the untransfected tumor, showed that the initial release of cytokine usually triggered an inflammatory reaction (13Colombo M.P. Forni G. Immunotherapy I cytokine gene transfer strategies.Cancer Metastasis Rev. 1997; 16: 421-432Crossref PubMed Google Scholar). This was followed by an influx of granulocytes. The cytokine and granulocytes were responsible for the debulking phase of the tumor rejection. Some aspect of the occurrence of this rejection process then induced a specific antitumor T cell response, which completed the rejection and produced a state of long-lived tumor immunity. Successful immunotherapy in many cases seems to be reduced to the problem of creating the right inflammatory reaction. Unfortunately, defining the elements of inflammation critical for the induction of tumor immunity and making them effective has been difficult. Some tumors spontaneously induce inflammation, but that is not necessarily indicative of a good prognosis. Intratumoral injection of nonspecific inflammatory inducers like BCG can sometimes suppress tumor growth, but it has not proven clinically useful, except in bladder cancer. It is likely that what is needed will vary from tumor to tumor, depending on the intrinsic strength of the tumor antigens, the APCs present at the tumor site, and the involvement of tumor-specific factors. Giving molecular definition to the widely accepted but hazy concept that an inflammatory environment is required for induction and persistence of an antitumor reaction is a major goal of tumor immunology. Even if the inherent properties of the normal immune system that make tumor cells generally nonimmunogenic are identified and circumvented, the tumor itself may still present additional obstacles to effective immunotherapy. Genomic instability is a property of tumor cells, and this facilitates loss of specific gene expression. In the effector phase of an antitumor response directed against a single antigen, the loss of expression of antigen, a necessary major histocompatibility complex (MHC) restricting element, or the transporter associated with antigen processing (TAP) could be critical. All of these losses do occur in tumors (67Uyttenhove C. Maryanski J. B" @default.
• W192003713 created "2016-06-24" @default.
• W192003713 creator A5060214926 @default.
• W192003713 date "1998-12-01" @default.
• W192003713 modified "2023-10-18" @default.
• W192003713 title "Tumor Immunology" @default.
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