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Immune Microenvironment in Tumor Progression: Characteristics and Challenges for Therapy

DOI: 10.1155/2012/608406

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The tumor microenvironment plays a critical role in cancer development, progression, and control. The molecular and cellular nature of the tumor immune microenvironment influences disease outcome by altering the balance of suppressive versus cytotoxic responses in the vicinity of the tumor. Recent developments in systems biology have improved our understanding of the complex interactions between tumors and their immunological microenvironment in various human cancers. Effective tumor surveillance by the host immune system protects against disease, but chronic inflammation and tumor “immunoediting” have also been implicated in disease development and progression. Accordingly, reactivation and maintenance of appropriate antitumor responses within the tumor microenvironment correlate with a good prognosis in cancer patients. Improved understanding of the factors that shape the tumor microenvironment will be critical for the development of effective future strategies for disease management. The manipulation of these microenvironmental factors is already emerging as a promising tool for novel cancer treatments. In this paper, we summarize the various roles of the tumor microenvironment in cancer, focusing on immunological mediators of tumor progression and control, as well as the significant challenges for future therapies. 1. Introduction The tumor microenvironment consists of cancer cells, stromal tissue, and extracellular matrix. The immune system is an important determinant of the tumor microenvironment. Indeed, the complex interplay between cancer cells and the host immune response has been extensively investigated in the past few decades. Several immunological deficiencies have been linked with enhanced tumor development in mouse models as well as in humans [1, 2]. The higher incidence of cancers in transplant patients receiving long-term immunosuppressive treatment is well documented [3–5]. Similarly, mice with compromised immune functions due to genetic modifications develop more tumors [6–9]. It is now well recognized that effective tumor surveillance by the immune system is critical to maintain homeostasis in the host. Despite exerting a key role in host protection, tumor surveillance by the immune system may eventually fail. As described in the three “Es” of cancer immunoediting, tumor cells are initially eliminated by the immune system before becoming clinically detectable. This is then followed by an equilibrium phase, where a selection process for less immunogenic tumor variants take place until the tumors finally “escape” the immune


[1]  M. T. Chow, A. M?ller, and M. J. Smyth, “Inflammation and immune surveillance in cancer,” Seminars in Cancer Biology, vol. 22, no. 1, pp. 23–32, 2012.
[2]  M. J. Smyth, G. P. Dunn, and R. D. Schreiber, “Cancer immunosurveillance and immunoediting: the roles of immunity in suppressing tumor development and shaping tumor immunogenicity,” Advances in Immunology, vol. 90, pp. 1–50, 2006.
[3]  S. Euvrard, J. Kanitakis, and A. Claudy, “Skin cancers after organ transplantation,” New England Journal of Medicine, vol. 348, no. 17, pp. 1681–1691, 2003.
[4]  E. Q. Sanchez, S. Marubashi, G. Jung et al., “De novo tumors after liver transplantation: a single-institution experience,” Liver Transplantation, vol. 8, no. 3, pp. 285–291, 2002.
[5]  F. O. Zwald, L. J. Christenson, E. M. Billingsley et al., “Melanoma in solid organ transplant recipients,” American Journal of Transplantation, vol. 10, no. 5, pp. 1297–1304, 2010.
[6]  M. Girardi, D. E. Oppenheim, C. R. Steele et al., “Regulation of cutaneous malignancy by γδ T cells,” Science, vol. 294, no. 5542, pp. 605–609, 2001.
[7]  M. J. Smyth, K. Y. T. Thia, S. E. A. Street et al., “Differential tumor surveillance by natural killer (NK) and NKT cells,” Journal of Experimental Medicine, vol. 191, no. 4, pp. 661–668, 2000.
[8]  S. E. A. Street, E. Cretney, and M. J. Smyth, “Perforin and interferon-γ activities independently control tumor initiation, growth, and metastasis,” Blood, vol. 97, no. 1, pp. 192–197, 2001.
[9]  M. F. Van Den Broek, D. K?gi, F. Ossendorp et al., “Decreased tumor surveillance in perforin-deficient mice,” Journal of Experimental Medicine, vol. 184, no. 5, pp. 1781–1790, 1996.
[10]  G. P. Dunn, A. T. Bruce, H. Ikeda, L. J. Old, and R. D. Schreiber, “Cancer immunoediting: from immunosurveillance to tumor escape,” Nature Immunology, vol. 3, no. 11, pp. 991–998, 2002.
[11]  A. M. Engel, I. M. Svane, J. Rygaard, and O. Werdelin, “MCA sarcomas induced in scid mice are more immunogenic than MCA sarcomas induced in congenic, immunocompetent mice,” Scandinavian Journal of Immunology, vol. 45, no. 5, pp. 463–470, 1997.
[12]  B. B. Aggarwal, “Inflammation, a silent killer in cancer is not so silent!,” Current Opinion in Pharmacology, vol. 9, no. 4, pp. 347–350, 2009.
[13]  B. B. Aggarwal, S. Shishodia, S. K. Sandur, M. K. Pandey, and G. Sethi, “Inflammation and cancer: how hot is the link?” Biochemical Pharmacology, vol. 72, no. 11, pp. 1605–1621, 2006.
[14]  F. Balkwill and A. Mantovani, “Inflammation and cancer: back to Virchow?” The Lancet, vol. 357, no. 9255, pp. 539–545, 2001.
[15]  V. Chew, J. Chen, D. Lee et al., “Chemokine-driven lymphocyte infiltration: an early intratumoural event determining long-term survival in resectable hepatocellular carcinoma,” Gut, vol. 61, no. 3, pp. 427–438, 2012.
[16]  D. S. Hsu, M. K. Kim, B. S. Balakumaran et al., “Immune signatures predict prognosis in localized cancer,” Cancer Investigation, vol. 28, no. 7, pp. 765–773, 2010.
[17]  K. Suzuki, S. S. Kachala, K. Kadota et al., “Prognostic immune markers in non-small cell lung cancer,” Clinical Cancer Research, vol. 17, no. 16, pp. 5247–5256, 2011.
[18]  F. Pagès, J. Galon, M. C. Dieu-Nosjean, E. Tartour, C. Sautès-Fridman, and W. H. Fridman, “Immune infiltration in human tumors: a prognostic factor that should not be ignored,” Oncogene, vol. 29, no. 8, pp. 1093–1102, 2010.
[19]  V. Chew, C. Tow, M. Teo et al., “Inflammatory tumour microenvironment is associated with superior survival in hepatocellular carcinoma patients,” Journal of Hepatology, vol. 52, no. 3, pp. 370–379, 2010.
[20]  C. E. Weber and P. C. Kuo, “The tumor microenvironment,” Surgical Oncology. In press.
[21]  Z. N. Oltvai and A. L. Barabási, “Systems biology: life's complexity pyramid,” Science, vol. 298, no. 5594, pp. 763–764, 2002.
[22]  N. A. Bhowmick, E. G. Neilson, and H. L. Moses, “Stromal fibroblasts in cancer initiation and progression,” Nature, vol. 432, no. 7015, pp. 332–337, 2004.
[23]  P. Carmeliet and R. K. Jain, “Angiogenesis in cancer and other diseases,” Nature, vol. 407, no. 6801, pp. 249–257, 2000.
[24]  S. M. Weis and D. A. Cheresh, “Tumor angiogenesis: molecular pathways and therapeutic targets,” Nature Medicine, vol. 17, no. 11, pp. 1359–1370, 2011.
[25]  J. P. Sleeman and W. Thiele, “Tumor metastasis and the lymphatic vasculature,” International Journal of Cancer, vol. 125, no. 12, pp. 2747–2756, 2009.
[26]  A. B. Mohseny and P. C. W. Hogendoorn, “Concise review: mesenchymal tumors: when stem cells go mad,” Stem Cells, vol. 29, no. 3, pp. 397–403, 2011.
[27]  S. Ostrand-Rosenberg and P. Sinha, “Myeloid-derived suppressor cells: linking inflammation and cancer,” Journal of Immunology, vol. 182, no. 8, pp. 4499–4506, 2009.
[28]  A. Mantovani, T. Schioppa, C. Porta, P. Allavena, and A. Sica, “Role of tumor-associated macrophages in tumor progression and invasion,” Cancer and Metastasis Reviews, vol. 25, no. 3, pp. 315–322, 2006.
[29]  M. Tosolini, A. Kirilovsky, B. Mlecnik et al., “Clinical impact of different classes of infiltrating T cytotoxic and helper cells (Th1, Th2, Treg, Th17) in patients with colorectal cancer,” Cancer Research, vol. 71, no. 4, pp. 1263–1271, 2011.
[30]  J. Wilson and F. Balkwill, “The role of cytokines in the epithelial cancer microenvironment,” Seminars in Cancer Biology, vol. 12, no. 2, pp. 113–120, 2002.
[31]  F. Balkwill, “Cancer and the chemokine network,” Nature Reviews Cancer, vol. 4, no. 7, pp. 540–550, 2004.
[32]  P. Matzinger, “The danger model: a renewed sense of self,” Science, vol. 296, no. 5566, pp. 301–305, 2002.
[33]  G. P. Sims, D. C. Rowe, S. T. Rietdijk, R. Herbst, and A. J. Coyle, “HMGB1 and RAGE in inflammation and cancer,” Annual Review of Immunology, vol. 28, pp. 367–388, 2010.
[34]  N. Bercovici and A. Trautmann, “Revisiting the role of T cells in tumor regression,” OncoImmunology, vol. 1, no. 3, pp. 346–350, 2012.
[35]  M. Melbye, T. R. Cote, L. Kessler, M. Gail, and R. J. Biggar, “High incidence of anal cancer among AIDS patients,” The Lancet, vol. 343, no. 8898, pp. 636–639, 1994.
[36]  D. C. Strauss and J. M. Thomas, “Transmission of donor melanoma by organ transplantation,” The Lancet Oncology, vol. 11, no. 8, pp. 790–796, 2010.
[37]  A. Stojanovic and A. Cerwenka, “Natural killer cells and solid tumors,” Journal of Innate Immunity, vol. 3, no. 4, pp. 355–364, 2011.
[38]  H. F. Pross and E. Lotzova, “Role of natural killer cells in cancer,” Natural Immunity, vol. 12, no. 4-5, pp. 279–292, 1993.
[39]  B. Weigelin, M. Krause, and P. Friedl, “Cytotoxic T lymphocyte migration and effector function in the tumor microenvironment,” Immunology Letters, vol. 138, no. 1, pp. 19–21, 2011.
[40]  T. W. H. Flinsenberg, E. B. Compeer, J. J. Boelens, and M. Boes, “Antigen cross-presentation: extending recent laboratory findings to therapeutic intervention,” Clinical and Experimental Immunology, vol. 165, no. 1, pp. 8–18, 2011.
[41]  Z. Qin, J. Schwartzkopff, F. Pradera et al., “A critical requirement of interferon γ-mediated angiostasis for tumor rejection by CD8+ T cells,” Cancer Research, vol. 63, no. 14, pp. 4095–4100, 2003.
[42]  D. J. DiLillo, K. Yanaba, and T. F. Tedder, “B cells are required for optimal CD4+ and CD8+ T cell tumor immunity: therapeutic B cell depletion enhances B16 melanoma growth in mice,” Journal of Immunology, vol. 184, no. 7, pp. 4006–4016, 2010.
[43]  N. Almog, “Molecular mechanisms underlying tumor dormancy,” Cancer Letters, vol. 294, no. 2, pp. 139–146, 2010.
[44]  J. Eyles, A. L. Puaux, X. Wang et al., “Tumor cells disseminate early, but immunosurveillance limits metastatic outgrowth, in a mouse model of melanoma,” Journal of Clinical Investigation, vol. 120, no. 6, pp. 2030–2039, 2010.
[45]  M. J. Browning and W. F. Bodmer, “MHC antigens and cancer: implications for T-cell surveillance,” Current Opinion in Immunology, vol. 4, no. 5, pp. 613–618, 1992.
[46]  J. C. Reed, “Mechanisms of apoptosis avoidance in cancer,” Current Opinion in Oncology, vol. 11, no. 1, pp. 68–75, 1999.
[47]  X. Zhang, D. Nie, and S. Chakrabarty, “Growth factors in tumor microenvironment,” Frontiers in Bioscience, vol. 15, no. 1, pp. 151–165, 2010.
[48]  A. Ben-Baruch, “Inflammation-associated immune suppression in cancer: the roles played by cytokines, chemokines and additional mediators,” Seminars in Cancer Biology, vol. 16, no. 1, pp. 38–52, 2006.
[49]  T. F. Gajewski, Y. Meng, and H. Harlin, “Immune suppression in the tumor microenvironment,” Journal of Immunotherapy, vol. 29, no. 3, pp. 233–240, 2006.
[50]  B. Huang, J. Zhao, H. Li et al., “Toll-like receptors on tumor cells facilitate evasion of immune surveillance,” Cancer Research, vol. 65, no. 12, pp. 5009–5014, 2005.
[51]  S. Goel, D. G. Duda, L. Xu et al., “Normalization of the vasculature for treatment of cancer and other diseases,” Physiological Reviews, vol. 91, no. 3, pp. 1071–1121, 2011.
[52]  W. Zou, “Regulatory T cells, tumour immunity and immunotherapy,” Nature Reviews Immunology, vol. 6, no. 4, pp. 295–307, 2006.
[53]  G. W. Middleton, N. E. Annels, and H. S. Pandha, “Are we ready to start studies of Th17 cell manipulation as a therapy for cancer?” Cancer Immunology, Immunotherapy, vol. 61, no. 1, pp. 1–7, 2012.
[54]  P. B. Olkhanud, B. Damdinsuren, M. Bodogai et al., “Tumor-evoked regulatory B cells promote breast cancer metastasis by converting resting CD4+ T cells to T-regulatory cells,” Cancer Research, vol. 71, no. 10, pp. 3505–3515, 2011.
[55]  F. I. Staquicini, A. Tandle, S. K. Libutti et al., “A subset of host B lymphocytes controls melanoma metastasis through a melanoma cell adhesion molecule/MUC18-dependent interaction: evidence from mice and humans,” Cancer Research, vol. 68, no. 20, pp. 8419–8428, 2008.
[56]  L. Yang and D. P. Carbone, “Tumor-host immune interactions and dendritic cell dysfunction,” Advances in Cancer Research, vol. 92, pp. 13–27, 2004.
[57]  I. Chemin and F. Zoulim, “Hepatitis B virus induced hepatocellular carcinoma,” Cancer Letters, vol. 286, no. 1, pp. 52–59, 2009.
[58]  M. Hatakeyama, “Helicobacter pylori and gastric carcinogenesis,” Journal of Gastroenterology, vol. 44, no. 4, pp. 239–248, 2009.
[59]  A. Mantovani, “Molecular pathways linking inflammation and cancer,” Current Molecular Medicine, vol. 10, no. 4, pp. 369–373, 2010.
[60]  D. R. Hodge, E. M. Hurt, and W. L. Farrar, “The role of IL-6 and STAT3 in inflammation and cancer,” European Journal of Cancer, vol. 41, no. 16, pp. 2502–2512, 2005.
[61]  A. S. Payne and L. A. Cornelius, “The role of chemokines in melanoma tumor growth and metastasis,” Journal of Investigative Dermatology, vol. 118, no. 6, pp. 915–922, 2002.
[62]  L. Yang, J. Huang, X. Ren et al., “Abrogation of TGFβ signaling in mammary carcinomas recruits Gr-1+CD11b+ myeloid cells that promote metastasis,” Cancer Cell, vol. 13, no. 1, pp. 23–35, 2008.
[63]  F. Balkwill, “The significance of cancer cell expression of the chemokine receptor CXCR4,” Seminars in Cancer Biology, vol. 14, no. 3, pp. 171–179, 2004.
[64]  Y. Ben-Neriah and M. Karin, “Inflammation meets cancer, with NF-κB as the matchmaker,” Nature Immunology, vol. 12, no. 8, pp. 715–723, 2011.
[65]  A. Jemal, R. Siegel, E. Ward et al., “Cancer statistics, 2008,” CA Cancer Journal for Clinicians, vol. 58, no. 2, pp. 71–96, 2008.
[66]  D. S. Micalizzi and H. L. Ford, “Epithelial-mesenchymal transition in development and cancer,” Future Oncology, vol. 5, no. 8, pp. 1129–1143, 2009.
[67]  J. P. Thiery, H. Acloque, R. Y. J. Huang, and M. A. Nieto, “Epithelial-mesenchymal transitions in development and disease,” Cell, vol. 139, no. 5, pp. 871–890, 2009.
[68]  P. Savagner, “The epithelial-mesenchymal transition (EMT) phenomenon,” Annals of Oncology, vol. 21, no. 7, pp. vii89–vii92, 2010.
[69]  B. Toh, X. Wang, J. Keeble et al., “Mesenchymal transition and dissemination of cancer cells is driven by myeloid-derived suppressor cells infiltrating the primary tumor,” PLoS Biology, vol. 9, no. 9, Article ID e1001162, 2011.
[70]  M. Santisteban, J. M. Reiman, M. K. Asiedu et al., “Immune-induced epithelial to mesenchymal transition in vivo generates breast cancer stem cells,” Cancer Research, vol. 69, no. 7, pp. 2887–2895, 2009.
[71]  A.-K. Bonde, V. Tischler, S. Kumar, A. Soltermann, and R. A. Schwendener, “Intratumoral macrophages contribute to epithelial-mesenchymal transition in solid tumors,” BMC Cancer, vol. 12, article 35, 2012.
[72]  E. Belnoue, C. Guettier, M. Kayibanda et al., “Regression of established liver tumor induced by monoepitopic peptide-based immunotherapy,” Journal of Immunology, vol. 173, no. 8, pp. 4882–4888, 2004.
[73]  S. B. Qian, Y. Li, G. X. Qian, and S. S. Chen, “Efficient tumor regression induced by genetically engineered tumor cells secreting interleukin-2 and membrane-expressing allogeneic MHC class I antigen,” Journal of Cancer Research and Clinical Oncology, vol. 127, no. 1, pp. 27–33, 2001.
[74]  Y. Hoshida, A. Villanueva, M. Kobayashi et al., “Gene expression in fixed tissues and outcome in hepatocellular carcinoma,” New England Journal of Medicine, vol. 359, no. 19, pp. 1995–2004, 2008.
[75]  A. Budhu, M. Forgues, Q. H. Ye et al., “Prediction of venous metastases, recurrence, and prognosis in hepatocellular carcinoma based on a unique immune response signature of the liver microenvironment,” Cancer Cell, vol. 10, no. 2, pp. 99–111, 2006.
[76]  J. Galon, A. Costes, F. Sanchez-Cabo et al., “Type, density, and location of immune cells within human colorectal tumors predict clinical outcome,” Science, vol. 313, no. 5795, pp. 1960–1964, 2006.
[77]  C. G. Clemente, M. C. Mihm Jr., R. Bufalino, S. Zurrida, P. Collini, and N. Cascinelli, “Prognostic value of tumor infiltrating lymphocytes in the vertical growth phase of primary cutaneous melanoma,” Cancer, vol. 77, no. 7, pp. 1303–1310, 1996.
[78]  R. A. Menegaz, M. A. Michelin, R. M. Etchebehere, P. C. Fernandes, and E. F. C. Murta, “Peri- and intratumoral T and B lymphocytic infiltration in breast cancer,” European Journal of Gynaecological Oncology, vol. 29, no. 4, pp. 321–326, 2008.
[79]  L. Zhang, J. R. Conejo-Garcia, D. Katsaros et al., “Intratumoral T cells, recurrence, and survival in epithelial ovarian cancer,” New England Journal of Medicine, vol. 348, no. 3, pp. 203–213, 2003.
[80]  M. C. Dieu-Nosjean, M. Antoine, C. Danel et al., “Long-term survival for patients with non-small-cell lung cancer with intratumoral lymphoid structures,” Journal of Clinical Oncology, vol. 26, no. 27, pp. 4410–4417, 2008.
[81]  L. Martinet, I. Garrido, T. Filleron et al., “Human solid tumors contain high endothelial venules: association with T- and B-lymphocyte infiltration and favorable prognosis in breast cancer,” Cancer Research, vol. 71, no. 17, pp. 5678–5687, 2011.
[82]  C. Schneider, A. Teufel, T. Yevsa, et al., “Adaptive immunity suppresses formation and progression of diethylnitrosamine-induced liver cancer,” Gut 2012. In press.
[83]  H. Harlin, Y. Meng, A. C. Peterson et al., “Chemokine expression in melanoma metastases associated with CD8+ T-CeII recruitment,” Cancer Research, vol. 69, no. 7, pp. 3077–3085, 2009.
[84]  S. Hirano, Y. Iwashita, A. Sasaki, S. Kai, M. Ohta, and S. Kitano, “Increased mRNA expression of chemokines in hepatocellular carcinoma with tumor-infiltrating lymphocytes,” Journal of Gastroenterology and Hepatology, vol. 22, no. 5, pp. 690–696, 2007.
[85]  M. Hong, A.-L. Puaux, C. Huang et al., “Chemotherapy induces intratumoral expression of chemokines in cutaneous melanoma, favoring T-cell infiltration and tumor control,” Cancer Research, vol. 71, no. 22, pp. 6997–7009, 2011.
[86]  K. Koizumi, S. Hojo, T. Akashi, K. Yasumoto, and I. Saiki, “Chemokine receptors in cancer metastasis and cancer cell-derived chemokines in host immune response,” Cancer Science, vol. 98, no. 11, pp. 1652–1658, 2007.
[87]  A. M. Fulton, “The chemokine receptors CXCR4 and CXCR3 in cancer,” Current Oncology Reports, vol. 11, no. 2, pp. 125–131, 2009.
[88]  S. A. Quezada, K. S. Peggs, T. R. Simpson, and J. P. Allison, “Shifting the equilibrium in cancer immunoediting: from tumor tolerance to eradication,” Immunological Reviews, vol. 241, no. 1, pp. 104–118, 2011.
[89]  T. F. Gajewski, “Cancer immunotherapy,” Molecular Oncology, vol. 6, no. 2, pp. 242–250, 2012.
[90]  A. Mantovani, P. Romero, A. K. Palucka, and F. M. Marincola, “Tumour immunity: effector response to tumour and role of the microenvironment,” The Lancet, vol. 371, no. 9614, pp. 771–783, 2008.
[91]  B. Bodey, “Spontaneous regression of neoplasms: new possibilities for immunotherapy,” Expert Opinion on Biological Therapy, vol. 2, no. 5, pp. 459–476, 2002.
[92]  L. V. Kalialis, K. T. Drzewiecki, and H. Klyver, “Spontaneous regression of metastases from melanoma: review of the literature,” Melanoma Research, vol. 19, no. 5, pp. 275–282, 2009.
[93]  F. Saleh, W. Renno, I. Klepacek et al., “Direct evidence on the immune-mediated spontaneous regression of human cancer: an incentive for pharmaceutical companies to develop novel anti-cancer vaccine,” Current Pharmaceutical Design, vol. 11, no. 27, pp. 3531–3543, 2005.
[94]  S. A. Rosenberg and M. E. Dudley, “Adoptive cell therapy for the treatment of patients with metastatic melanoma,” Current Opinion in Immunology, vol. 21, no. 2, pp. 233–240, 2009.
[95]  A. Gillgrass and A. Ashkar, “Stimulating natural killer cells to protect against cancer: recent developments,” Expert Review of Clinical Immunology, vol. 7, no. 3, pp. 367–382, 2011.
[96]  S. K. Lee and S. Gasser, “The role of natural killer cells in cancer therapy,” Frontiers in Bioscience, vol. 2, pp. 380–391, 2010.
[97]  K. L. Alderson and P. M. Sondel, “Clinical cancer therapy by NK cells via antibody-dependent cell-mediated cytotoxicity,” Journal of Biomedicine and Biotechnology, vol. 2011, Article ID 379123, 7 pages, 2011.
[98]  T. H. Schreiber, L. Raez, J. D. Rosenblatt, and E. R. Podack, “Tumor immunogenicity and responsiveness to cancer vaccine therapy: the state of the art,” Seminars in Immunology, vol. 22, no. 3, pp. 105–112, 2010.
[99]  C. L. Slingluff, “The present and future of peptide vaccines for cancer: single or multiple, long or short, alone or in combination?” Cancer Journal, vol. 17, no. 5, pp. 343–350, 2011.
[100]  P. W. Kantoff, C. S. Higano, N. D. Shore et al., “Sipuleucel-T immunotherapy for castration-resistant prostate cancer,” New England Journal of Medicine, vol. 363, no. 5, pp. 411–422, 2010.
[101]  G. Farrell, “Prevention of hepatocellular carcinoma in the Asia-Pacific region: consensus statements,” Journal of Gastroenterology and Hepatology, vol. 25, no. 4, pp. 657–663, 2010.
[102]  M. A. Kane, “Global implementation of human papillomavirus (HPV) vaccine: lessons from hepatitis B vaccine,” Gynecologic Oncology, vol. 117, no. 2, pp. S32–S35, 2010.
[103]  M. H. Chang, “Hepatitis B virus and cancer prevention,” Recent Results in Cancer Research, vol. 188, pp. 75–84, 2011.
[104]  A. E. Albers, B. Sinikovi?, A. V. Banko, S. Jovanovi?, and A. M. Kaufmann, “Developments in therapeutic human papillomavirus vaccination,” Acta chirurgica Iugoslavica, vol. 56, no. 3, pp. 29–37, 2009.
[105]  R. Roden, A. Monie, and T. C. Wu, “The impact of preventive HPV vaccination,” Discovery medicine, vol. 6, no. 35, pp. 175–181, 2006.
[106]  F. Moschella, E. Proietti, I. Capone, and F. Belardelli, “Combination strategies for enhancing the efficacy of immunotherapy in cancer patients,” Annals of the New York Academy of Sciences, vol. 1194, pp. 169–178, 2010.
[107]  G. K. Antony and A. Z. Dudek, “Interleukin 2 in cancer therapy,” Current Medicinal Chemistry, vol. 17, no. 29, pp. 3297–3302, 2010.
[108]  A. J. Grillo-López, C. A. White, B. K. Dallaire et al., “Rituximab: the first monoclonal antibody approved for the treatment of lymphoma,” Current Pharmaceutical Biotechnology, vol. 1, no. 1, pp. 1–9, 2000.
[109]  G. N. Hortobagyi, “Trastuzumab in the treatment of breast cancer,” New England Journal of Medicine, vol. 353, no. 16, pp. 1734–1736, 2005.
[110]  A. L. D. De Cerio, N. Zabalegui, M. Rodríguez-Calvillo, S. Inogés, and M. Bendandi, “Anti-idiotype antibodies in cancer treatment,” Oncogene, vol. 26, no. 25, pp. 3594–3602, 2007.
[111]  T. Meyer and E. Stockfleth, “Clinical investigations of Toll-like receptor agonists,” Expert Opinion on Investigational Drugs, vol. 17, no. 7, pp. 1051–1065, 2008.
[112]  S. Adams, “Toll-like receptor agonists in cancer therapy,” Immunotherapy, vol. 1, no. 6, pp. 949–964, 2009.
[113]  S. M. Garland, “Imiquimod,” Current Opinion in Infectious Diseases, vol. 16, no. 2, pp. 85–89, 2003.
[114]  M. Urosevic and R. Dummer, “Role of imiquimod in skin cancer treatment,” American Journal of Clinical Dermatology, vol. 5, no. 6, pp. 453–458, 2004.
[115]  B. Rubin and J. E. Gairin, “Concepts and ways to amplify the antitumor immune response,” Current Topics in Microbiology and Immunology, vol. 344, pp. 97–128, 2011.
[116]  S. E. Braun, K. Chen, R. G. Foster et al., “The CC chemokine CKβ-11/MIP-3β/ELC/exodus 3 mediates tumor rejection of murine breast cancer cells through NK cells,” Journal of Immunology, vol. 164, no. 8, pp. 4025–4031, 2000.
[117]  L. Baitsch, P. Baumgaertner, E. Devêvre et al., “Exhaustion of tumor-specific CD8+ T cells in metastases from melanoma patients,” Journal of Clinical Investigation, vol. 121, no. 6, pp. 2350–2360, 2011.
[118]  C. A. Klebanoff, N. Acquavella, Z. Yu, and N. P. Restifo, “Therapeutic cancer vaccines: are we there yet?” Immunological Reviews, vol. 239, no. 1, pp. 27–44, 2011.
[119]  F. Hirano, K. Kaneko, H. Tamura et al., “Blockade of B7-H1 and PD-1 by monoclonal antibodies potentiates cancer therapeutic immunity,” Cancer Research, vol. 65, no. 3, pp. 1089–1096, 2005.
[120]  G. Dotti, “Blocking PD-1 in cancer immunotherapy,” Blood, vol. 114, no. 8, pp. 1457–1458, 2009.
[121]  E. J. Lipson and C. G. Drake, “Ipilimumab: an anti-CTLA-4 antibody for metastatic melanoma,” Clinical Cancer Research, vol. 17, no. 22, pp. 6958–6962, 2011.
[122]  P. A. Prieto, J. C. Yang, R. M. Sherry et al., “CTLA-4 blockade with ipilimumab: long-term follow-up of 177 patients with metastatic melanoma,” Clinical Cancer Research, vol. 18, no. 7, pp. 2039–2047, 2012.
[123]  P. DeLong, T. Tanaka, R. Kruklitis et al., “Use of cyclooxygenase-2 inhibition to enhance the efficacy of immunotherapy,” Cancer Research, vol. 63, no. 22, pp. 7845–7852, 2003.
[124]  W. Dempke, C. Rie, A. Grothey, and H. J. Schmoll, “Cyclooxygenase-2: a novel target for cancer chemotherapy?” Journal of Cancer Research and Clinical Oncology, vol. 127, no. 7, pp. 411–417, 2001.
[125]  J. Dannull, Z. Su, D. Rizzieri et al., “Enhancement of vaccine-mediated antitumor immunity in cancer patients after depletion of regulatory T cells,” Journal of Clinical Investigation, vol. 115, no. 12, pp. 3623–3633, 2005.
[126]  M. A. Morse, A. C. Hobeika, T. Osada et al., “Depletion of human regulatory T cells specifically enhances antigen-specific immune responses to cancer vaccines,” Blood, vol. 112, no. 3, pp. 610–618, 2008.
[127]  N. Woller, S. Knocke, B. Mundt et al., “Virus-induced tumor inflammation facilitates effective DC cancer immunotherapy in a Treg-dependent manner in mice,” Journal of Clinical Investigation, vol. 121, no. 7, pp. 2570–2582, 2011.
[128]  L. Zitvogel, L. Apetoh, F. Ghiringhelli, F. André, A. Tesniere, and G. Kroemer, “The anticancer immune response: indispensable for therapeutic success?” Journal of Clinical Investigation, vol. 118, no. 6, pp. 1991–2001, 2008.
[129]  V. P. Balachandran, M. J. Cavnar, S. Zeng et al., “Imatinib potentiates antitumor T cell responses in gastrointestinal stromal tumor through the inhibition of Ido,” Nature Medicine, vol. 17, no. 9, pp. 1094–1100, 2011.
[130]  Q. Li, R. R. Rao, K. Araki et al., “A central role for mTOR kinase in homeostatic proliferation induced CD8+ T cell memory and tumor immunity,” Immunity, vol. 34, no. 4, pp. 541–553, 2011.
[131]  S. Gasser and D. Raulet, “The DNA damage response, immunity and cancer,” Seminars in Cancer Biology, vol. 16, no. 5, pp. 344–347, 2006.
[132]  L. Zitvogel, O. Kepp, and G. Kroemer, “Immune parameters affecting the efficacy of chemotherapeutic regimens,” Nature Reviews Clinical Oncology, vol. 8, no. 3, pp. 151–160, 2011.
[133]  G. Bocci, K. C. Nicolaou, and R. S. Kerbel, “Protracted low-dose effects on human endothelial cell proliferation and survival in vitro reveal a selective antiangiogenic window for various chemotherapeutic drugs,” Cancer Research, vol. 62, no. 23, pp. 6938–6943, 2002.
[134]  R. A. Lake and B. W. S. Robinson, “Immunotherapy and chemotherapy—a practical partnership,” Nature Reviews Cancer, vol. 5, no. 5, pp. 397–405, 2005.


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