Cancer and Metastasis Reviews

, Volume 33, Issue 2–3, pp 737–745 | Cite as

Immune regulation of therapy-resistant niches: emerging targets for improving anticancer drug responses



Emerging evidence has unveiled a critical role for immunological parameters in predicting tumor prognosis and clinical responses to anticancer therapeutics. On the other hand, responsiveness to anticancer drugs greatly modifies the repertoires, phenotypes, and immunogenicity of tumor-infiltrating immune cells, serving as a critical factor to regulate tumorigenic activities and the emergence of therapy-resistant phenotypes. Tumor-associated immune functions are influenced by distinct or overlapping sets of therapeutic modalities, such as cytotoxic chemotherapy, radiotherapy, or molecular-targeted therapy, and various anticancer modalities have unique properties to influence the mode of cross-talk between tumor cells and immune cells in tumor microenvironments. Thus, it is critical to understand precise molecular machineries whereby each anticancer strategy has a distinct or overlapping role in regulating the dynamism of reciprocal communication between tumor and immune cells in tumor microenvironments. Such an understanding will open new therapeutic opportunities by harnessing the immune system to overcome resistance to conventional anticancer drugs.


Anticancer drug resistance Intratumor immune response Chemotherapy Radiotherapy Molecular targeting 


  1. 1.
    Higgins, C. F. (2007). Multiple molecular mechanisms for multidrug resistance transporters. Nature, 446, 749–757.PubMedCrossRefGoogle Scholar
  2. 2.
    Reya, T., Morrison, S. J., Clarke, M. F., & Weissman, I. L. (2001). Stem cells, cancer, and cancer stem cells. Nature, 414, 105–111.PubMedCrossRefGoogle Scholar
  3. 3.
    Sharma, S. V., Lee, D. Y., Li, B., Quinlan, M. P., Takahashi, F., Maheswaran, S., et al. (2010). A chromatin-mediated reversible drug-tolerant state in cancer cell subpopulations. Cell, 141, 69–80.PubMedCrossRefPubMedCentralGoogle Scholar
  4. 4.
    Holohan, C., Van Schaeybroeck, S., Longley, D. B., & Johnston, P. G. (2013). Cancer drug resistance: an evolving paradigm. Nature Reviews Cancer, 13, 714–726.PubMedCrossRefGoogle Scholar
  5. 5.
    Roesch, A., Fukunaga-Kalabis, M., Schmidt, E. C., Zabierowski, S. E., Brafford, P. A., Vultur, A., et al. (2010). A temporarily distinct subpopulation of slow-cycling melanoma cells is required for continuous tumor growth. Cell, 141, 583–594.PubMedCrossRefPubMedCentralGoogle Scholar
  6. 6.
    Roesch, A., Vultur, A., Bogeski, I., Wang, H., Zimmermann, K. M., Speicher, D., et al. (2013). Overcoming intrinsic multidrug resistance in melanoma by blocking the mitochondrial respiratory chain of slow-cycling JARID1B(high) cells. Cancer Cell, 23, 811–825.PubMedCrossRefGoogle Scholar
  7. 7.
    Magee, J. A., Piskounova, E., & Morrison, S. J. (2012). Cancer stem cells: impact, heterogeneity, and uncertainty. Cancer Cell, 21, 283–296.PubMedCrossRefGoogle Scholar
  8. 8.
    Clevers, H. (2011). The cancer stem cell: premises, promises and challenges. Nature Medicine, 17, 313–319.PubMedCrossRefGoogle Scholar
  9. 9.
    Haber, D. A., Bell, D. W., Sordella, R., Kwak, E. L., Godin-Heymann, N., Sharma, S. V., et al. (2005). Molecular targeted therapy of lung cancer: EGFR mutations and response to EGFR inhibitors. Cold Spring Harbor Symposia on Quantitative Biology, 70, 419–426.PubMedCrossRefGoogle Scholar
  10. 10.
    Poulikakos, P. I., & Rosen, N. (2011). Mutant BRAF melanomas—dependence and resistance. Cancer Cell, 19(1), 11–15.PubMedCrossRefGoogle Scholar
  11. 11.
    Nahta, R., Yu, D., Hung, M. C., Hortobagyi, G. N., & Esteva, F. J. (2006). Mechanisms of disease: understanding resistance to HER2-targeted therapy in human breast cancer. Nature Clinical Practice Oncology, 3(5), 269–280.PubMedCrossRefGoogle Scholar
  12. 12.
    Gilbert, L. A., & Hemann, M. T. (2010). DNA damage-mediated induction of a chemoresistant niche. Cell, 143, 355–366.PubMedCrossRefPubMedCentralGoogle Scholar
  13. 13.
    Pallasch, C. P., Leskov, I., Braun, C. J., Vorholt, D., Drake, A., & Soto-Feliciano, Y. M. (2014). Sensitizing protective tumor microenvironments to antibody-mediated therapy. Cell, 156(3), 590–602.PubMedCrossRefGoogle Scholar
  14. 14.
    Farmer, P., Bonnefoi, H., Anderle, P., Cameron, D., Wirapati, P., Becette, V., et al. (2009). A stroma-related signature predicts resistance to neoadjuvant chemotherapy in breast cancer. Nature Medicine, 15, 68–74.PubMedCrossRefGoogle Scholar
  15. 15.
    Iliopoulos, D., Hirsch, H. A., & Struhl, K. (2010). An epigenetic switch involving NF-kB, Lin28, Let-7 MicroRNA, and IL-6 links inflammation to cell transformation. Cell, 139, 693–706.CrossRefGoogle Scholar
  16. 16.
    Gilvennikov, S. I., Greten, F. R., & Karin, M. (2010). Immunity, inflammation, and cancer. Cell, 140, 883–899.CrossRefGoogle Scholar
  17. 17.
    Lake, R. A., & Robinson, B. W. (2005). Immunotherapy and chemotherapy—a practical partnership. Nature Reviews Cancer, 5(5), 397–405.PubMedCrossRefGoogle Scholar
  18. 18.
    Zitvogel, L., Galluzzi, L., Smyth, M. J., & Kroemer, G. (2013). Mechanism of action of conventional and targeted anticancer therapies: reinstating immunosurveillance. Immunity, 39, 74–88.PubMedCrossRefGoogle Scholar
  19. 19.
    Jinushi, M., Yagita, H., Yoshiyama, H., & Tahara, H. (2013). Putting the brakes on anticancer therapies: suppression of innate immune pathways by tumor-associated myeloid cells. Trends in Molecular Medicine, 9, 536–545.CrossRefGoogle Scholar
  20. 20.
    Bruchard, M., Mignot, G., Derangère, V., Chalmin, F., Chevriaux, A., Végran, F., et al. (2013). Chemotherapy-triggered cathepsin B release in myeloid-derived suppressor cells activates the Nlrp3 inflammasome and promotes tumor growth. Nature Medicine, 19(1), 57–64.PubMedCrossRefGoogle Scholar
  21. 21.
    Huang, B., Zhao, J., Li, H., He, K. L., Chen, Y., & Chen, S. H. (2005). Toll-like receptors on tumor cells facilitate evasion of immune surveillance. Cancer Research, 65(12), 5009–5014.PubMedCrossRefGoogle Scholar
  22. 22.
    Huang, B., Zhao, J., Unkeless, J. C., Feng, Z. H., & Xiong, H. (2008). TLR signaling by tumor and immune cells: a double-edged sword. Oncogene, 27(2), 218–224.PubMedCrossRefGoogle Scholar
  23. 23.
    Dranoff, G. (2004). Cytokines in cancer pathogenesis and cancer therapy. Nature Reviews Cancer, 4, 11–22.PubMedCrossRefGoogle Scholar
  24. 24.
    Lin, W. W., & Karin, M. (2007). A cytokine-mediated link between innate immunity, inflammation, and cancer. Journal of Clinical Investigation, 117, 1175–1183.PubMedCrossRefPubMedCentralGoogle Scholar
  25. 25.
    Tye, H., Kennedy, C. L., Najdovska, M., McLeod, L., McCormack, W., Hughes, N., et al. (2012). STAT3-driven upregulation of TLR2 promotes gastric tumorigenesis independent of tumor inflammation. Cancer Cell, 22(4), 466–478.PubMedCrossRefGoogle Scholar
  26. 26.
    Huang, B., Zhao, J., Shen, S., Li, H., He, K. L., Shen, G. X., et al. (2007). Listeria monocytogenes promotes tumor growth via tumor cell toll-like receptor 2 signaling. Cancer Research, 67(9), 4346–4352.PubMedCrossRefGoogle Scholar
  27. 27.
    Szajnik, M., Szczepanski, M. J., Czystowska, M., Elishaev, E., Mandapathil, M., Nowak-Markwitz, E., et al. (2009). TLR4 signaling induced by lipopolysaccharide or paclitaxel regulates tumor survival and chemoresistance in ovarian cancer. Oncogene, 28, 4353–4563.PubMedCrossRefPubMedCentralGoogle Scholar
  28. 28.
    Cherfils-Vicini, J., Platonova, S., Gillard, M., Laurans, L., Validire, P., Caliandro, R., et al. (2010). Triggering of TLR7 and TLR8 expressed by human lung cancer cells induces cell survival and chemoresistance. Journal of Clinical Investigation, 120, 1285–1297.PubMedCrossRefPubMedCentralGoogle Scholar
  29. 29.
    Chiba, S., Baghdadi, M., Akiba, H., Yoshiyama, H., Kinoshita, I., Dosaka-Akita, H., et al. (2012). Tumor-infiltrating DCs suppress nucleic acid-mediated innate immune responses through interactions between the receptor TIM-3 and the alarmin HMGB1. Nature Immunology, 13, 832–842.PubMedCrossRefPubMedCentralGoogle Scholar
  30. 30.
    Tang, D., & Lotze, M. T. (2012). Tumor immunity times out: TIM-3 and HMGB1. Nature Immunology, 9, 808–810.CrossRefGoogle Scholar
  31. 31.
    Green, D. R., et al. (2009). Immunogenic and tolerogenic cell death. Nature Reviews Immunology, 9, 353–363.PubMedCrossRefPubMedCentralGoogle Scholar
  32. 32.
    Obeid, M., et al. (2007). Calreticulin exposure dictates the immunogenicity of cancer cell death. Nature Medicine, 13, 54–61.PubMedCrossRefGoogle Scholar
  33. 33.
    Jinushi, M., et al. (2009). Milk fat globule EGF-8 triggers tumor destruction through coordinated cell-autonomous and immune-mediated mechanisms. Journal of Experimental Medicine, 206, 1317–1326.PubMedCrossRefPubMedCentralGoogle Scholar
  34. 34.
    Loges, S., Schmidt, T., Tjwa, M., van Geyte, K., Lievens, D., Lutgens, E., et al. (2010). Malignant cells fuel tumor growth by educating infiltrating leukocytes to produce the mitogen Gas6. Blood, 115(11), 2264–2273.PubMedCrossRefGoogle Scholar
  35. 35.
    Elliott, M. R., Chekeni, F. B., Trampont, P. C., Lazarowski, E. R., Kadl, A., Walk, S. F., et al. (2009). Nucleotides released by apoptotic cells act as a find-me signal to promote phagocytic clearance. Nature, 461(7261), 282–286.PubMedCrossRefPubMedCentralGoogle Scholar
  36. 36.
    Chao, M. P., Majeti, R., & Weissman, I. L. (2011). Programmed cell removal: a new obstacle in the road to developing cancer. Nature Reviews Cancer, 12, 58–67.PubMedGoogle Scholar
  37. 37.
    Chao, M. P., Jaiswal, S., Weissman-Tsukamoto, R., Alizadeh, A. A., Gentles, A. J., Volkmer, J., et al. (2010). Calreticulin is the dominant pro-phagocytic signal on multiple human cancers and counterbalanced by CD47. Science Translational Medicine, 2(63), 63ra94.PubMedCrossRefGoogle Scholar
  38. 38.
    Jaiswal, S., Jamieson, C. H., Pang, W. W., Park, C. Y., Chao, M. P., Majeti, R., et al. (2009). CD47 is upregulated on circulating hematopoietic stem cells and leukemia cells to avoid phagocytosis. Cell, 138(2), 271–285.PubMedCrossRefPubMedCentralGoogle Scholar
  39. 39.
    Baghdadi, M., Yoneda, A., Yamashina, T., Nagao, H., Komohara, Y., Nagai, S., et al. (2013). TIM-4 glycoprotein-mediated degradation of dying tumor cells by autophagy leads to reduced antigen presentation and increased immune tolerance. Immunity, 39, 1070–1081.PubMedCrossRefGoogle Scholar
  40. 40.
    Jinushi, M., Chiba, S., Baghdadi, M., Kinoshita, I., Dosaka-Akita, H., Ito, K., et al. (2012). ATM-mediated DNA damage signals mediate immune escape through integrin-αvβ3-dependent mechanisms. Cancer Research, 72(1), 56–65.PubMedCrossRefGoogle Scholar
  41. 41.
    Di Micco, R., Fumagalli, M., Cicalese, A., Piccinin, S., Gasparini, P., Luise, C., et al. (2006). Oncogene-induced senescence is a DNA damage response triggered by DNA hyper-replication. Nature, 444, 638–642.PubMedCrossRefGoogle Scholar
  42. 42.
    Mooi, W. J., & Peeper, D. S. (2006). Oncogene-induced cell senescence—halting on the road to cancer. New England Journal of Medicine, 355, 1037–1046.PubMedCrossRefGoogle Scholar
  43. 43.
    Collado, M., Blasco, M. A., & Serrano, M. (2007). Cellular senescence in cancer and aging. Cell, 130, 223–233.PubMedCrossRefGoogle Scholar
  44. 44.
    Kuilman, T., & Peeper, D. S. (2009). Senescence-messaging secretome: SMS-ing cellular stress. Nature Reviews Cancer, 9(2), 81–94.PubMedCrossRefGoogle Scholar
  45. 45.
    Coppé, J. P., Desprez, P. Y., Krtolica, A., & Campisi, J. (2010). The senescence-associated secretory phenotype: the dark side of tumor suppression. Annual Review of Pathology, 5, 99–118.PubMedCrossRefGoogle Scholar
  46. 46.
    Acosta, J. C., Banito, A., Wuestefeld, T., Georgilis, A., Janich, P., & Morton, J. P. (2013). A complex secretory program orchestrated by the inflammasome controls paracrine senescence. Nature Cell Biology, 8, 978–990.CrossRefGoogle Scholar
  47. 47.
    Kuilman, T., Michaloglou, C., Vredeveld, L. C., Douma, S., van Doorn, R., Desmet, C. J., et al. (2008). Oncogene-induced senescence relayed by an interleukin-dependent inflammatory network. Cell, 133(6), 1019–1031.PubMedCrossRefGoogle Scholar
  48. 48.
    Pazolli, E., Alspach, E., Milczarek, A., Prior, J., Piwnica-Worms, D., & Stewart, S. A. (2012). Chromatin remodeling underlies the senescence-associated secretory phenotype of tumor stromal fibroblasts that supports cancer progression. Cancer Research, 72(9), 225122–225161.CrossRefGoogle Scholar
  49. 49.
    Canino, C., Mori, F., Cambria, A., Diamantini, A., Germoni, S., Alessandrini, G., et al. (2012). SASP mediates chemoresistance and tumor-initiating-activity of mesothelioma cells. Oncogene, 31(26), 3148–3163.PubMedCrossRefGoogle Scholar
  50. 50.
    Yoshimoto, S., Loo, T. M., Atarashi, K., Kanda, H., Sato, S., Oyadomari, S., et al. (2013). Obesity-induced gut microbial metabolite promotes liver cancer through senescence secretome. Nature, 499, 97–101.PubMedCrossRefGoogle Scholar
  51. 51.
    Lujambio, A., Akkari, L., Simon, J., Grace, D., Tschaharganeh, D. F., & Bolden, J. E. (2013). Non-cell-autonomous tumor suppression by p53. Cell, 153, 449–460.PubMedCrossRefPubMedCentralGoogle Scholar
  52. 52.
    Xue, W., Zender, L., Miething, C., Dickins, R. A., Hernando, E., Krizhanovsky, V., et al. (2007). Senescence and tumour clearance is triggered by p53 restoration in murine liver carcinomas. Nature, 445(7128), 656–660.PubMedCrossRefGoogle Scholar
  53. 53.
    Chien, Y., Scuoppo, C., Wang, X., Fang, X., Balgley, B., Bolden, J. E., et al. (2012). Control of the senescence-associated secretory phenotype by NF-κB promotes senescence and enhances chemosensitivity. Genes and Development, 25(20), 2125–2136.CrossRefGoogle Scholar
  54. 54.
    Formenti, S. C., & Demaria, S. (2009). Systemic effects of local radiotherapy. Lancet Oncology, 10(7), 718–726.PubMedCrossRefPubMedCentralGoogle Scholar
  55. 55.
    Klug, F., Prakash, H., Huber, P. E., Seibel, T., Bender, N., Halama, N., et al. (2013). Low-dose irradiation programs macrophage differentiation to an iNOS+/M1 phenotype that orchestrates effective T cell immunotherapy. Cancer Cell, 24(5), 589–602.PubMedCrossRefGoogle Scholar
  56. 56.
    Burnette, B. C., Liang, H., Lee, Y., Chlewicki, L., Khodarev, N. N., Weichselbaum, R. R., et al. (2011). The efficacy of radiotherapy relies upon induction of type i interferon-dependent innate and adaptive immunity. Cancer Research, 71(7), 2488–2496.PubMedCrossRefPubMedCentralGoogle Scholar
  57. 57.
    Lee, Y., Auh, S. L., Wang, Y., Burnette, B., Wang, Y., Meng, Y., et al. (2009). Therapeutic effects of ablative radiation on local tumor require CD8+ T cells: changing strategies for cancer treatment. Blood, 114(3), 589–595.PubMedCrossRefPubMedCentralGoogle Scholar
  58. 58.
    Takeshima, T., Chamoto, K., Wakita, D., Ohkuri, T., Togashi, Y., Shirato, H., et al. (2010). Local radiation therapy inhibits tumor growth through the generation of tumor-specific CTL: its potentiation by combination with Th1 cell therapy. Cancer Research, 70(7), 2697–2706.PubMedCrossRefGoogle Scholar
  59. 59.
    Ludgate, C. M. (2012). Optimizing cancer treatments to induce an acute immune response: radiation Abscopal effects, PAMPs, and DAMPs. Clinical Cancer Research, 18, 4522–4525.PubMedCrossRefGoogle Scholar
  60. 60.
    Apetoh, L., Ghiringhelli, F., Tesniere, A., Criollo, A., Ortiz, C., Lidereau, R., et al. (2007). The interaction between HMGB1 and TLR4 dictates the outcome of anticancer chemotherapy and radiotherapy. Immunology Reviews, 220, 47–59.CrossRefGoogle Scholar
  61. 61.
    Krysko, D. V., Garg, A. D., Kaczmarek, A., Krysko, O., Agostinis, P., & Vandenabeele, P. (2012). Immunogenic cell death and DAMPs in cancer therapy. Nature Reviews Cancer, 12, 860–875.PubMedCrossRefGoogle Scholar
  62. 62.
    Kozin, S. V., Duda, D. G., Munn, L. L., & Jain, R. K. (2012). Neovascularization after irradiation: what is the source of newly formed vessels in recurring tumors? Journal of the National Cancer Institute, 104, 899–905.PubMedCrossRefPubMedCentralGoogle Scholar
  63. 63.
    Xu, J., Escamilla, J., Mok, S., David, J., Priceman, S., West, B., et al. (2013). CSF1R signaling blockade stanches tumor-infiltrating myeloid cells and improves the efficacy of radiotherapy in prostate cancer. Cancer Research, 73(9), 2782–2794.PubMedCrossRefPubMedCentralGoogle Scholar
  64. 64.
    Sharma, S. V., Bell, D. W., Settleman, J., & Haber, D. A. (2007). Epidermal growth factor receptor mutations in lung cancer. Nature Reviews Cancer, 7(3), 169–181.PubMedCrossRefGoogle Scholar
  65. 65.
    Lynch, T. J., Bell, D. W., Sordella, R., Gurubhagavatula, S., Okimoto, R. A., Brannigan, B. W., et al. (2004). Activating mutations in the epidermal growth factor receptor underlying responsiveness of non-small-cell lung cancer to gefitinib. New England Journal of Medicine, 350(21), 2129–2139.PubMedCrossRefGoogle Scholar
  66. 66.
    Kobayashi, S., Boggon, T. J., Dayaram, T., Jänne, P. A., Kocher, O., Meyerson, M., et al. (2005). EGFR mutation and resistance of non-small-cell lung cancer to gefitinib. New England Journal of Medicine, 352(8), 786–792.PubMedCrossRefGoogle Scholar
  67. 67.
    Bivona, T. G., Hieronymus, H., Parker, J., Chang, K., Taron, M., Rosell, R., et al. (2011). FAS and NF-κB signalling modulate dependence of lung cancers on mutant EGFR. Nature, 47, 523–526.CrossRefGoogle Scholar
  68. 68.
    Engelman, J. A., Zejnullahu, K., Mitsudomi, T., Song, Y., Hyland, C., Park, J. O., et al. (2007). MET amplification leads to gefitinib resistance in lung cancer by activating ERBB3 signaling. Science, 316, 1039–1043.PubMedCrossRefGoogle Scholar
  69. 69.
    Vanneman, M., & Dranoff, G. (2012). Combining immunotherapy and targeted therapies in cancer treatment. Nature Reviews Cancer, 12(4), 237–251.PubMedCrossRefPubMedCentralGoogle Scholar
  70. 70.
    Gao, S. P., Mark, K. G., Leslie, K., Pao, W., Motoi, N., Gerald, W. L., et al. (2007). Mutations in the EGFR kinase domain mediate STAT3 activation via IL-6 production in human lung adenocarcinomas. Journal of Clinical Investigation, 117, 3846–3856.PubMedCrossRefPubMedCentralGoogle Scholar
  71. 71.
    Jinushi, M., Chiba, S., Yoshiyama, H., Masutomi, K., Kinoshita, I., Dosaka-Akita, H., et al. (2011). Tumor-associated macrophages regulate tumorigenicity and anticancer drug responses of cancer stem/initiating cells. Proceedings of the National Academy of Sciences of the United States of America, 108(30), 12425–12430.PubMedCrossRefPubMedCentralGoogle Scholar
  72. 72.
    Zhang, Z., Lee, J. C., Lin, L., Olivas, V., Au, V., LaFramboise, T., et al. (2012). Activation of the AXL kinase causes resistance to EGFR-targeted therapy in lung cancer. Nature Genetics, 44(8), 852–860.PubMedCrossRefPubMedCentralGoogle Scholar
  73. 73.
    Chapman, P. B., Hauschild, A., Robert, C., Haanen, J. B., Ascierto, P., Larkin, J., BRIM-3 Study Group, et al. (2011). Improved survival with vemurafenib in melanoma with BRAF V600E mutation. New England Journal of Medicine, 364, 2507–2516.PubMedCrossRefPubMedCentralGoogle Scholar
  74. 74.
    Sumimoto, H., Imabayashi, F., Iwata, T., & Kawakami, Y. (2006). The BRAF-MAPK signaling pathway is essential for cancer-immune evasion in human melanoma cells. Journal of Experimental Medicine, 203, 1651–1656.PubMedCrossRefPubMedCentralGoogle Scholar
  75. 75.
    Jiang, X., Zhou, J., Giobbie-Hurder, A., Wargo, J., & Hodi, F. S. (2013). The activation of MAPK in melanoma cells resistant to BRAF inhibition promotes PD-L1 expression that is reversible by MEK and PI3K inhibition. Clinical Cancer Research, 19, 598–609.PubMedCrossRefGoogle Scholar
  76. 76.
    Knight, D. A., Ngiow, S. F., Li, M., Parmenter, T., Mok, S., Cass, A., et al. (2013). Host immunity contributes to the anti-melanoma activity of BRAF inhibitors. Journal of Clinical Investigation, 123, 1371–1381.PubMedCrossRefPubMedCentralGoogle Scholar
  77. 77.
    Frederick, D. T., Piris, A., Cogdill, A. P., Cooper, Z. A., Lezcano, C., Ferrone, C. R., et al. (2013). BRAF inhibition is associated with enhanced melanoma antigen expression and a more favorable tumor microenvironment in patients with metastatic melanoma. Clinical Cancer Research, 19, 1225–1231.PubMedCrossRefPubMedCentralGoogle Scholar
  78. 78.
    Hudes, G., Carducci, M., Tomczak, P., Dutcher, J., Figlin, R., Kapoor, A., Global ARCC Trial, et al. (2007). Temsirolimus, interferon alfa, or both for advanced renal-cell carcinoma. New England Journal of Medicine, 356, 2271–2281.PubMedCrossRefGoogle Scholar
  79. 79.
    Pearce, E. L., & Pearce, E. J. (2013). Metabolic pathways in immune cell activation and quiescence. Immunity, 38, 633–643.PubMedCrossRefPubMedCentralGoogle Scholar
  80. 80.
    Waickman, A. T., & Powell, J. D. (2012). mTOR, metabolism, and the regulation of T-cell differentiation and function. Immunology Reviews, 49, 43–58.CrossRefGoogle Scholar
  81. 81.
    Amiel, E., Everts, B., Freitas, T. C., King, I. L., Curtis, J. D., Pearce, E. L., et al. (2012). Inhibition of mechanistic target of rapamycin promotes dendritic cell activation and enhances therapeutic autologous vaccination in mice. Journal of Immunology, 189, 2151–2158.CrossRefGoogle Scholar
  82. 82.
    Berezhnoy, A., Castro, I., Levay, A., Malek, T. R., & Gilboa, E. (2014). Aptamer-targeted inhibition of mTOR in T cells enhances antitumor immunity. Journal of Clinical Investigation, 124, 188–197.PubMedCrossRefPubMedCentralGoogle Scholar
  83. 83.
    Bianchini, G., & Gianni, L. (2014). The immune system and response to HER2-targeted treatment in breast cancer. Lancet Oncology, 2, e58–e68.CrossRefGoogle Scholar
  84. 84.
    Taylor, C., Hershman, D., Shah, N., Suciu-Foca, N., Petrylak, D. P., Taub, R., et al. (2007). Augmented HER-2 specific immunity during treatment with trastuzumab and chemotherapy. Clinical Cancer Research, 13, 5133–5143.PubMedCrossRefGoogle Scholar
  85. 85.
    DeNardo, D. G., Brennan, D. J., Rexhepaj, E., Ruffell, B., Shiao, S. L., Madden, S. F., et al. (2011). Leukocyte complexity predicts breast cancer survival and functionally regulates response to chemotherapy. Cancer Discovery, 1(1), 54–67.PubMedCrossRefPubMedCentralGoogle Scholar
  86. 86.
    Kohrt, H. E., Nouri, N., Nowels, K., Johnson, D., Holmes, S., & Lee, P. P. (2005). Profile of immune cells in axillary lymph nodes predicts disease-free survival in breast cancer. PLoS Medicine, 2(9), e284.PubMedCrossRefPubMedCentralGoogle Scholar
  87. 87.
    Hideshima, T., Mitsiades, C., Tonon, G., Richardson, P. G., & Anderson, K. C. (2007). Understanding multiple myeloma pathogenesis in the bone marrow to identify new therapeutic targets. Nature Reviews Cancer, 8, 585–598.CrossRefGoogle Scholar
  88. 88.
    Richardson, P. G., Sonneveld, P., Schuster, M. W., Irwin, D., Stadtmauer, E. A., Facon, T., Assessment of Proteasome Inhibition for Extending Remissions (APEX) Investigators, et al. (2005). Bortezomib or high-dose dexamethasone for relapsed multiple myeloma. New England Journal of Medicine, 352, 2487–2498.PubMedCrossRefGoogle Scholar
  89. 89.
    Palumbo, A., Hajek, R., Delforge, M., Kropff, M., Petrucci, M. T., Catalano, J., MM-015 Investigators, et al. (2012). Continuous lenalidomide treatment for newly diagnosed multiple myeloma. New England Journal of Medicine, 366, 1759–1769.PubMedCrossRefGoogle Scholar
  90. 90.
    Chauhan, D., Singh, A. V., Brahmandam, M., Carrasco, R., Bandi, M., Hideshima, T., et al. (2009). Functional interaction of plasmacytoid dendritic cells with multiple myeloma cells: a therapeutic target. Cancer Cell, 16, 309–323.PubMedCrossRefPubMedCentralGoogle Scholar
  91. 91.
    Jinushi, M., Vanneman, M., Munshi, N. C., Tai, Y. T., Prabhala, R. H., Ritz, J., et al. (2008). MHC class I chain-related protein A antibodies and shedding are associated with the progression of multiple myeloma. Proceedings of the National Academy of Sciences of the United States of America, 105, 1285–1290.PubMedCrossRefPubMedCentralGoogle Scholar
  92. 92.
    Martiniani, R., Di Loreto, V., Di Sano, C., Lombardo, A., & Liberati, A. M. (2012). Biological activity of lenalidomide and its underlying therapeutic effects in multiple myeloma. Advances in Hematology, 2012, 842945.PubMedCrossRefPubMedCentralGoogle Scholar
  93. 93.
    Ghiringhelli, F., Apetoh, L., Tesniere, A., Aymeric, L., Ma, Y., Ortiz, C., et al. (2009). Activation of the NLRP3 inflammasome in dendritic cells induces IL-1beta-dependent adaptive immunity against tumors. Nature Medicine, 15, 1170–1178.PubMedCrossRefGoogle Scholar
  94. 94.
    Yamamoto, R., Nishikori, M., Tashima, M., Sakai, T., Ichinohe, T., Takaori-Kondo, A., et al. (2009). B7-H1 expression is regulated by MEK/ERK signaling pathway in anaplastic large cell lymphoma and Hodgkin lymphoma. Cancer Science, 100, 2093–2100.PubMedCrossRefGoogle Scholar
  95. 95.
    Ribas, A., & Wolchok, J. D. (2013). Combining cancer immunotherapy and targeted therapy. Current Opinion in Immunology, 25, 291–296.PubMedCrossRefPubMedCentralGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2014

Authors and Affiliations

  1. 1.Research Center for Infection-associated Cancer, Institute for Genetic MedicineHokkaido UniversitySapporoJapan

Personalised recommendations