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Journal of Clinical Oncology, Vol 23, No 35 (December 10), 2005: pp. 8923-8925 © 2005 American Society of Clinical Oncology. DOI: 10.1200/JCO.2005.10.007
Global Role of the Immune System in Identifying Cancer Initiation and Limiting Disease Progression
Center for Translational Medicine in Women's Health, University of Washington, Seattle, WA The field of tumor immunology has undergone a significant scientific evolution during the last decade. We now know that human cancer is immunogenic, and we have identified a multitude of tumor-related proteins that stimulate immunity in cancer patients. Highly quantitative and reproducible methods for measuring immunity have been developed and have allowed a more complete delineation of the tumor-associated immune response. Functional antitumor immunity requires a response initiated by potent antigen-presenting cells, such as dendritic cells, and the engagement of a variety of effector cells—not only cytotoxic T cells, but also T-helper cells and B cells, which initiate antibody immunity. Finally, mechanisms of immune escape increasingly are being determined. Cancer evasion of the immune system is not only related to immunosuppressive factors secreted by the tumor and surrounding stroma, but is also aided by the fact that most tumor antigens are self-proteins. Self-proteins, as cancer antigens, impede the generation of robust immunity via toleragenic mechanisms, such as the elaboration of T-regulatory cells, which function to prevent autoimmunity and limit inflammation. The result of these advances in the laboratory is the development of immunotherapeutic strategies that are targeted, are tailored for specific disease burdens, and directly address mechanisms of immune system failure. The studies presented in this issue of the Journal of Clinical Oncology represent the diversity of clinical applications that are now possible when contemplating immune-based strategies for cancer patients. There is abundant evidence that tumor-specific immunity is present even in early-stage cancers. Human antibodies specific for tumor-related proteins, which are used to probe expression libraries developed from tumor cells, are an effective tool for identifying antigens.1 Recent data suggest that antibody immunity is so prevalent in cancer patients that an immunologic signature that would predict those who will develop cancer can be identified.2 Screening sera from prostate cancer patients and controls against 22 immunogenic peptides derived from prostate cancer tissue was a more sensitive test than the measurement of serum prostate-specific antigen levels for discriminating individuals with cancer from controls. Furthermore, evidence of an adaptive immune response at the site of a tumor has been shown to impact prognosis. Zhang et al3 demonstrated that infiltrating T cells observed in ovarian cancer tumors could be characterized as intratumoral or stromal. Those patients with T cells clearly invading the tumor bed had a significantly improved prognosis as compared with individuals whose T-cell infiltrates were located in the stroma. This survival benefit transcended optimal surgical debulking, a critical outcome predictor in ovarian cancer. Analysis of inflammatory infiltrates in non–small-cell lung cancer, presented in this issue of the Journal, demonstrates striking similarities to the observations in ovarian cancer, albeit with a measure of an innate immune response: the macrophage.4 Macrophage infiltrates could be detected in both tumor islets and the tumor stroma of non–small-cell lung cancers. Increasing macrophage density in tumor islets was an independent favorable prognostic indicator, whereas increasing macrophage stromal density was an independent predictor of reduced survival. The survival benefit associated with macrophage-infiltrating tumor cell islets was discernable even in those patients who had an incomplete resection of their tumor. These patients had a longer survival than those patients whose tumors were completely resected and had evidence of only low intratumoral macrophage infiltration. Such studies lay the foundation for diagnostic and prognostic approaches utilizing endogenous tumor-specific immunity and may ultimately help identify clinically important immunologic pathways that could lead to effective antitumor therapies. The role of the tumor microenvironment in dampening developing immunity cannot be overstated. Cytokines and chemokines elaborated by the tumor and stroma, suppressive antigen-presenting cells in the bed of the tumor, and other substances in the tumor environment that limit potentially productive inflammation all impact the efficacy of tumor immunotherapy.5,6 Several articles in this issue focus on the use of immunotherapy integrated with more standard forms of treatment. The integration of biologic therapies with conventional approaches may enhance tumor cell kill via a variety of mechanisms. Chemotherapy has been shown to potentially reduce the number of T-regulatory cells in the environment, promote the expansion of tumor specific memory T cells, and enhance the expression of immune-recognition molecules on the surface of the tumor cell.7 In addition, the type of cell death elicited by different chemotherapies, apoptotic versus nonapoptotic, may impact immunity induced by the dying tumor cell.8 In the past, conventional wisdom dictated that cytotoxic chemotherapy was immunosuppressive. Immune-based cancer therapies were evaluated frequently in more advanced stage patients who no longer responded to or needed chemotherapy. The results of these studies were often disappointing and not associated with significant clinical improvement. The use of chemobiotherapy will allow cytolytic reduction of tumor burden that, in itself, may augment endogenous immunity. Combination strategies that aim to systemically enhance the immune response and directly modulate the tumor microenvironment via more standard agents may provide a "hit" to the cancer cell along separate and nonredundant pathways, thus optimizing cell kill. As the tumor grows, the ability of the immune system to overcome the cancer fades. A recent comprehensive review of multiple studies of active immunization in advanced-stage melanoma patients demonstrated that vaccines resulted in a clinical response rate much less than 10% in most studies.9 Vaccine approaches have been developed to address multiple mechanisms of potential immune failure. The study in this issue by van Baren et al targeted an antigen broadly expressed in melanoma, MAGE, and involved immunizing patients with advanced-stage melanoma. In addition, the antigen was delivered via a recombinant canary pox vector that would allow intracellular delivery of the specific epitopes, processing via the class I pathway, and the generation of cytotoxic T cells. Although the vaccine focused on a common antigen and utilized a state-of-the-art immunization platform, tumor-specific cytotoxic immunity was detected in only a minority of patients. Furthermore, clinical responses were rare. Such data have resulted in a re-evaluation of the role of cancer vaccines in the treatment of progressive cancer. Clinical trials of therapeutic cancer vaccines are now being designed to target minimal residual disease with the overall goal of determining whether active immunization can be used to prevent disease relapse, and this approach appears promising.10,11 Clearly, cancer can be prevented via immunologic manipulation. The use of either an HPV-16 vaccine or a quadrivalent HPV (-6, -11, -16, -18) vaccine resulted in remarkable protection against the development of cervical cancer in sexually active young adults.12,13 The combination of targeting vaccines to low-burden disease or high-risk populations as well as using newer vaccine technologies to make self–tumor proteins appear more dangerous to the immune system, as dangerous as a virus, will certainly optimize clinical results. Immunotherapeutic strategies can also be developed for refractory advanced stage disease. Adoptive T-cell therapy involves the ex vivo expansion of tumor-specific T cells to large numbers and infusion of those T cells into patients. This type of approach can achieve levels of immunity that cannot be reached via active immunization alone. In this issue, Comoli et al demonstrate that treatment of nasopharyngeal carcinoma with EBV-specific T cells is feasible and potentially useful in controlling disease progression.14 Other studies have shown the utility of T-cell transfer in melanoma.15 Competent tumor-specific T cells are capable of mediating an antitumor response and persisting for an extended period in vivo. Over the next several years, we will continue to see immunotherapeutic strategies being applied to the clinic, based on the level of tumor burden the immune system will need to eradicate. More rational clinical applications, coupled with treatment strategies based on immunologic scientific advances, are likely to result in immune therapies that improve clinical outcomes for cancer patients. The last decade of both basic and clinical research in the field of tumor immunology has brought us to a crossroads where the bench and the bedside merge. The most important studies over the next several years will be the ones that evaluate immunologic principles in the patient by analyzing both clinical responses and therapeutic mechanisms of action. Only then will clinical trials of immunotherapy advance into standard clinical practice. Authors' Disclosures of Potential Conflicts of Interest The authors indicated no potential conflicts of interest. REFERENCES 1. Preuss KD, Zwick C, Bormann C, et al: Analysis of the B-cell repertoire against antigens expressed by human neoplasms. Immunol Rev 188:43-50, 2002[CrossRef][Medline] 2. Wang X, Yu J, Sreekumar A, et al: Autoantibody signatures in prostate cancer. N Engl J Med 353:1224-1235, 2005 3. Zhang L, Conejo-Garcia JR, Katsaros D, et al: Intratumoral T cells, recurrence, and survival in epithelial ovarian cancer. N Engl J Med 348:203-213, 2003 4. Peoples GE, Gurney JM, Hueman MT, et al: Clinical trial results of a HER2/neu (E75) vaccine to prevent recurrence in high-risk breast cancer patients. J Clin Oncol 23:7536-7545, 2005 5. Zou W: Immunosuppressive networks in the tumour environment and their therapeutic relevance. Nat Rev Cancer 5:263-274, 2005[CrossRef][Medline] 6. Balkwill F, Charles KA, Mantovani A: Smoldering and polarized inflammation in the initiation and promotion of malignant disease. Cancer Cell 7:211-217, 2005[CrossRef][Medline] 7. Emens LA, Jaffee EM: Leveraging the activity of tumor vaccines with cytotoxic chemotherapy. Cancer Res 65:8059-8064, 2005 8. Lake RA, Robinson BW: Immunotherapy and chemotherapy–a practical partnership. Nat Rev Cancer 5:397-405, 2005[CrossRef][Medline] 9. Banchereau J, Palucka AK: Dendritic cells as therapeutic vaccines against cancer. Nat Rev Immunol 5:296-306, 2005[CrossRef][Medline] 10. Sosman JA, Unger JM, Liu PY, et al: Adjuvant immunotherapy of resected, intermediate-thickness, node- negative melanoma with an allogeneic tumor vaccine: Impact of HLA class I antigen expression on outcome. J Clin Oncol 20:2067-2075, 2002 11. Peoples GE, Gurney JM, Hueman MT, et al: Clinical trial results of a HER2/neu (E75) vaccine to prevent recurrence in high-risk breast cancer patients. J Clin Oncol, 2005 12. Koutsky LA, Ault KA, Wheeler CM, et al: A controlled trial of a human papillomavirus type 16 vaccine. N Engl J Med 347:1645-1651, 2002 13. Villa LL, Costa RL, Petta CA, et al: Prophylactic quadrivalent human papillomavirus (types 6, 11, 16, and 18) L1 virus-like particle vaccine in young women: A randomised double-blind placebo-controlled multicentre phase II efficacy trial. Lancet Oncol 6:271-278, 2005[CrossRef][Medline] 14. Comoli P, Pedrazzoli P, Maccario R, et al: Cell therapy of stage IV nasopharyngeal carcinoma with autologous Epstein-Barr virus–targeted cytotoxic T lymphocytes. J Clin Oncol 23:8942-8949, 2005 15. Dudley ME, Wunderlich JR, Yang JC, et al: Adoptive cell transfer therapy following non-myeloablative but lymphodepleting chemotherapy for the treatment of patients with refractory metastatic melanoma. J Clin Oncol 23:2346-2357, 2005 This article has been cited by other articles:
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Copyright © 2005 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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