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
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.