Advertisement

Cancer and Metastasis Reviews

, Volume 30, Issue 1, pp 71–82 | Cite as

How to improve the immunogenicity of chemotherapy and radiotherapy

  • Yuting Ma
  • Rosa Conforti
  • Laetitia Aymeric
  • Clara Locher
  • Oliver Kepp
  • Guido Kroemer
  • Laurence Zitvogel
Article

Abstract

Chemotherapy or radiotherapy could induce various tumor cell death modalities, releasing tumor-derived antigen as well as danger signals that could either be captured for triggering antitumor immune response or ignored. Exploring the interplay among therapeutic drugs, tumor cell death and the immune cells should improve diagnostic, prognostic, predictive, and therapeutic management of tumor. We summarized some of the cell death-derived danger signals and the mechanism for host to sense and response to cell death in the tumor microenvironment. Based on the recent clinical or experimental findings, several strategies have been suggested to improve the immunogenicity of cell death and augment antitumor immunity.

Keywords

Cell death DAMP Tumor microenvironment Immune cells 

Abbreviations

DC

Dendritic cells

ALK

Anaplastic lymphoma kinase

ALCL

Anaplastic large cell lymphoma

DAMP

Damage-associated molecular patterns

HSP

Heat shock proteins

LysoPC

Lysophosphatidylcholine

HMGB1

High-mobility group box 1 protein

CRT

Calreticulin

ER

Endoplasmic reticulum

Tim

T cell immunoglobulin mucin

Mincle

Macrophage-inducible C-type lectin

SAP130

Spliceosome-associated protein 130

MDSCs

Myeloid-derived suppressor cells

DNAM-1

DNAX accessory molecule-1

SAP130

Spliceosome-associated protein 130

Treg

Regulatory T cells

MDR

Multidrug resistance

CTX

Cyclophosphamide

TSC

Tumor stem cells

DLN

Draining lymph node

IDO

Indoleamine-pyrrole 2,3-dioxygenase

Notes

Acknowledgment

The authors thank INFLA-CARE FP7 EU grant, INCa, Fondation pourla Recherche Médicale, and Fondation de France. YM was supported by China Scholarship Council.

References

  1. 1.
    Hodi, F. S., & Dranoff, G. (2006). Combinatorial cancer immunotherapy. Advances in Immunology, 90, 341–368. doi: 10.1016/S0065-2776(06)90009-1.PubMedGoogle Scholar
  2. 2.
    Soiffer, R., Hodi, F. S., Haluska, F., Jung, K., Gillessen, S., Singer, S., et al. (2003). Vaccination with irradiated, autologous melanoma cells engineered to secrete granulocyte–macrophage colony-stimulating factor by adenoviral-mediated gene transfer augments antitumor immunity in patients with metastatic melanoma. Journal of Clinical Oncology, 21(17), 3343–3350. doi: 10.1200/JCO.2003.07.005.PubMedGoogle Scholar
  3. 3.
    Salgia, R., Lynch, T., Skarin, A., Lucca, J., Lynch, C., Jung, K., et al. (2003). Vaccination with irradiated autologous tumor cells engineered to secrete granulocyte–macrophage colony-stimulating factor augments antitumor immunity in some patients with metastatic non-small-cell lung carcinoma. Journal of Clinical Oncology, 21(4), 624–630.PubMedGoogle Scholar
  4. 4.
    Perez, C. A., Fu, A., Onishko, H., Hallahan, D. E., & Geng, L. (2009). Radiation induces an antitumour immune response to mouse melanoma. International Journal of Radiation Biology, 85(12), 1126–1136. doi: 10.3109/09553000903242099.PubMedGoogle Scholar
  5. 5.
    Casares, N., Pequignot, M. O., Tesniere, A., Ghiringhelli, F., Roux, S., Chaput, N., et al. (2005). Caspase-dependent immunogenicity of doxorubicin-induced tumor cell death. The Journal of Experimental Medicine, 202(12), 1691–1701. doi: 10.1084/jem.20050915.PubMedGoogle Scholar
  6. 6.
    Obeid, M., Tesniere, A., Ghiringhelli, F., Fimia, G. M., Apetoh, L., Perfettini, J. L., et al. (2007). Calreticulin exposure dictates the immunogenicity of cancer cell death. Natural Medicines, 13(1), 54–61. doi: 10.1038/nm1523.Google Scholar
  7. 7.
    Chiarle, R., Martinengo, C., Mastini, C., Ambrogio, C., D’Escamard, V., Forni, G., et al. (2008). The anaplastic lymphoma kinase is an effective oncoantigen for lymphoma vaccination. Natural Medicines, 14(6), 676–680. doi: 10.1038/nm1769.Google Scholar
  8. 8.
    Correale, P., Cusi, M. G., Tsang, K. Y., Del Vecchio, M. T., Marsili, S., Placa, M. L., et al. (2005). Chemo-immunotherapy of metastatic colorectal carcinoma with gemcitabine plus FOLFOX 4 followed by subcutaneous granulocyte macrophage colony-stimulating factor and interleukin-2 induces strong immunologic and antitumor activity in metastatic colon cancer patients. Journal of Clinical Oncology, 23(35), 8950–8958. doi: 10.1200/JCO.2005.12.147.PubMedGoogle Scholar
  9. 9.
    Ma, Y., Kepp, O., Ghiringhelli, F., Apetoh, L., Aymeric, L., Locher, C., et al. (2010). Chemotherapy and radiotherapy: Cryptic anticancer vaccines. Seminars in Immunology, 22(3), 113–124. doi: 10.1016/j.smim.2010.03.001.PubMedGoogle Scholar
  10. 10.
    Imaeda, A. B., Watanabe, A., Sohail, M. A., Mahmood, S., Mohamadnejad, M., Sutterwala, F. S., et al. (2009). Acetaminophen-induced hepatotoxicity in mice is dependent on Tlr9 and the Nalp3 inflammasome. Journal of Clinical Investigation, 119(2), 305–314. doi: 10.1172/JCI35958.PubMedGoogle Scholar
  11. 11.
    Scaffidi, P., Misteli, T., & Bianchi, M. E. (2002). Release of chromatin protein HMGB1 by necrotic cells triggers inflammation. Nature, 418(6894), 191–195. doi: 10.1038/nature00858.PubMedGoogle Scholar
  12. 12.
    Yamasaki, S., Ishikawa, E., Sakuma, M., Hara, H., Ogata, K., & Saito, T. (2008). Mincle is an ITAM-coupled activating receptor that senses damaged cells. Nature Immunology, 9(10), 1179–1188. doi: 10.1038/ni.1651.PubMedGoogle Scholar
  13. 13.
    Foell, D., Wittkowski, H., Vogl, T., & Roth, J. (2007). S100 proteins expressed in phagocytes: A novel group of damage-associated molecular pattern molecules. Journal of Leukocyte Biology, 81(1), 28–37. doi: 10.1189/jlb.0306170.PubMedGoogle Scholar
  14. 14.
    Barrat, F. J., Meeker, T., Gregorio, J., Chan, J. H., Uematsu, S., Akira, S., et al. (2005). Nucleic acids of mammalian origin can act as endogenous ligands for Toll-like receptors and may promote systemic lupus erythematosus. The Journal of Experimental Medicine, 202(8), 1131–1139. doi: 10.1084/jem.20050914.PubMedGoogle Scholar
  15. 15.
    Osterloh, A., Veit, A., Gessner, A., Fleischer, B., & Breloer, M. (2008). Hsp60-mediated T cell stimulation is independent of TLR4 and IL-12. International Immunology, 20(3), 433–443. doi: 10.1093/intimm/dxn003.PubMedGoogle Scholar
  16. 16.
    Basu, S., Binder, R. J., Ramalingam, T., & Srivastava, P. K. (2001). CD91 is a common receptor for heat shock proteins gp96, hsp90, hsp70, and calreticulin. Immunity, 14(3), 303–313.PubMedGoogle Scholar
  17. 17.
    Rock, K. L., Latz, E., Ontiveros, F., & Kono, H. (2010). The sterile inflammatory response. Annual Review of Immunology, 28, 321–342. doi: 10.1146/annurev-immunol-030409-101311.PubMedGoogle Scholar
  18. 18.
    Chen, C. J., Kono, H., Golenbock, D., Reed, G., Akira, S., & Rock, K. L. (2007). Identification of a key pathway required for the sterile inflammatory response triggered by dying cells. Natural Medicines, 13(7), 851–856. doi: 10.1038/nm1603.Google Scholar
  19. 19.
    Distler, J. H., Huber, L. C., Gay, S., Distler, O., & Pisetsky, D. S. (2006). Microparticles as mediators of cellular cross-talk in inflammatory disease. Autoimmunity, 39(8), 683–690. doi: 10.1080/08916930601061538.PubMedGoogle Scholar
  20. 20.
    Peter, C., Waibel, M., Radu, C. G., Yang, L. V., Witte, O. N., Schulze-Osthoff, K., et al. (2008). Migration to apoptotic “find-me” signals is mediated via the phagocyte receptor G2A. The Journal of Biological Chemistry, 283(9), 5296–5305. doi: 10.1074/jbc.M706586200.PubMedGoogle Scholar
  21. 21.
    Lauber, K., Bohn, E., Krober, S. M., Xiao, Y. J., Blumenthal, S. G., Lindemann, R. K., et al. (2003). Apoptotic cells induce migration of phagocytes via caspase-3-mediated release of a lipid attraction signal. Cell, 113(6), 717–730.PubMedGoogle Scholar
  22. 22.
    Yang, D., Chen, Q., Yang, H., Tracey, K. J., Bustin, M., & Oppenheim, J. J. (2007). High mobility group box-1 protein induces the migration and activation of human dendritic cells and acts as an alarmin. Journal of Leukocyte Biology, 81(1), 59–66. doi: 10.1189/jlb.0306180.PubMedGoogle Scholar
  23. 23.
    Orlova, V. V., Choi, E. Y., Xie, C., Chavakis, E., Bierhaus, A., Ihanus, E., et al. (2007). A novel pathway of HMGB1-mediated inflammatory cell recruitment that requires Mac-1-integrin. The EMBO Journal, 26(4), 1129–1139. doi: 10.1038/sj.emboj.7601552.PubMedGoogle Scholar
  24. 24.
    Apetoh, L., Ghiringhelli, F., Tesniere, A., Obeid, M., Ortiz, C., Criollo, A., et al. (2007). Toll-like receptor 4-dependent contribution of the immune system to anticancer chemotherapy and radiotherapy. Natural Medicines, 13(9), 1050–1059. doi: 10.1038/nm1622.Google Scholar
  25. 25.
    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. doi: 10.1038/nature08296.PubMedGoogle Scholar
  26. 26.
    Gude, D. R., Alvarez, S. E., Paugh, S. W., Mitra, P., Yu, J., Griffiths, R., et al. (2008). Apoptosis induces expression of sphingosine kinase 1 to release sphingosine-1-phosphate as a “come-and-get-me” signal. The FASEB Journal, 22(8), 2629–2638. doi: 10.1096/fj.08-107169.PubMedGoogle Scholar
  27. 27.
    Mesaeli, N., & Phillipson, C. (2004). Impaired p53 expression, function, and nuclear localization in calreticulin-deficient cells. Molecular Biology of the Cell, 15(4), 1862–1870. doi: 10.1091/mbc.E03-04-0251.PubMedGoogle Scholar
  28. 28.
    Gardai, S. J., McPhillips, K. A., Frasch, S. C., Janssen, W. J., Starefeldt, A., Murphy-Ullrich, J. E., et al. (2005). Cell-surface calreticulin initiates clearance of viable or apoptotic cells through trans-activation of LRP on the phagocyte. Cell, 123(2), 321–334. doi: 10.1016/j.cell.2005.08.032.PubMedGoogle Scholar
  29. 29.
    Obeid, M., Tesniere, A., Panaretakis, T., Tufi, R., Joza, N., van Endert, P., et al. (2007). Ecto-calreticulin in immunogenic chemotherapy. Immunological Reviews, 220, 22–34. doi: 10.1111/j.1600-065X.2007.00567.x.PubMedGoogle Scholar
  30. 30.
    Obeid, M., Panaretakis, T., Joza, N., Tufi, R., Tesniere, A., van Endert, P., et al. (2007). Calreticulin exposure is required for the immunogenicity of gamma-irradiation and UVC light-induced apoptosis. Cell Death and Differentiation, 14(10), 1848–1850. doi: 10.1038/sj.cdd.4402201.PubMedGoogle Scholar
  31. 31.
    Panaretakis, T., Joza, N., Modjtahedi, N., Tesniere, A., Vitale, I., Durchschlag, M., et al. (2008). The co-translocation of ERp57 and calreticulin determines the immunogenicity of cell death. Cell Death and Differentiation, 15(9), 1499–1509. doi: 10.1038/cdd.2008.67.PubMedGoogle Scholar
  32. 32.
    Panaretakis, T., Kepp, O., Brockmeier, U., Tesniere, A., Bjorklund, A. C., Chapman, D. C., et al. (2009). Mechanisms of pre-apoptotic calreticulin exposure in immunogenic cell death. The EMBO Journal, 28(5), 578–590. doi: 10.1038/emboj.2009.1.PubMedGoogle Scholar
  33. 33.
    Garrido, C., Brunet, M., Didelot, C., Zermati, Y., Schmitt, E., & Kroemer, G. (2006). Heat shock proteins 27 and 70: Anti-apoptotic proteins with tumorigenic properties. Cell Cycle, 5(22), 2592–2601.PubMedGoogle Scholar
  34. 34.
    Lanneau, D., Brunet, M., Frisan, E., Solary, E., Fontenay, M., & Garrido, C. (2008). Heat shock proteins: Essential proteins for apoptosis regulation. Journal of Cellular and Molecular Medicine, 12(3), 743–761. doi: 10.1111/j.1582-4934.2008.00273.x.PubMedGoogle Scholar
  35. 35.
    Spisek, R., & Dhodapkar, M. V. (2007). Towards a better way to die with chemotherapy: Role of heat shock protein exposure on dying tumor cells. Cell Cycle, 6(16), 1962–1965.PubMedGoogle Scholar
  36. 36.
    Tesniere, A., Panaretakis, T., Kepp, O., Apetoh, L., Ghiringhelli, F., Zitvogel, L., et al. (2008). Molecular characteristics of immunogenic cancer cell death. Cell Death and Differentiation, 15(1), 3–12. doi: 10.1038/sj.cdd.4402269.PubMedGoogle Scholar
  37. 37.
    Doody, A. D., Kovalchin, J. T., Mihalyo, M. A., Hagymasi, A. T., Drake, C. G., & Adler, A. J. (2004). Glycoprotein 96 can chaperone both MHC class I- and class II-restricted epitopes for in vivo presentation, but selectively primes CD8+ T cell effector function. Journal of Immunology, 172(10), 6087–6092.Google Scholar
  38. 38.
    Murshid, A., Gong, J., & Calderwood, S. K. (2010). Heat shock protein 90 mediates efficient antigen cross presentation through the scavenger receptor expressed by endothelial cells-I. Journal of Immunology, 185(5), 2903–2917. doi: 10.4049/jimmunol.0903635.Google Scholar
  39. 39.
    Chan, T., Chen, Z., Hao, S., Xu, S., Yuan, J., Saxena, A., et al. (2007). Enhanced T-cell immunity induced by dendritic cells with phagocytosis of heat shock protein 70 gene-transfected tumor cells in early phase of apoptosis. Cancer Gene Therapy, 14(4), 409–420. doi: 10.1038/sj.cgt.7701025.PubMedGoogle Scholar
  40. 40.
    Elsner, L., Flugge, P. F., Lozano, J., Muppala, V., Eiz-Vesper, B., Demiroglu, S. Y., et al. (2010). The endogenous danger signals HSP70 and MICA cooperate in the activation of cytotoxic effector functions of NK cells. Journal of Cellular and Molecular Medicine, 14(4), 992–1002. doi: 10.1111/j.1582-4934.2009.00677.x.PubMedGoogle Scholar
  41. 41.
    Fionda, C., Soriani, A., Malgarini, G., Iannitto, M. L., Santoni, A., & Cippitelli, M. (2009). Heat shock protein-90 inhibitors increase MHC class I-related chain A and B ligand expression on multiple myeloma cells and their ability to trigger NK cell degranulation. Journal of Immunology, 183(7), 4385–4394. doi: 10.4049/jimmunol.0901797.Google Scholar
  42. 42.
    Dhodapkar, M. V., Dhodapkar, K. M., & Li, Z. (2008). Role of chaperones and FcgammaR in immunogenic death. Current Opinion in Immunology, 20(5), 512–517. doi: 10.1016/j.coi.2008.05.002.PubMedGoogle Scholar
  43. 43.
    Wang, X. Y., Sun, X., Chen, X., Facciponte, J., Repasky, E. A., Kane, J., et al. (2010). Superior antitumor response induced by large stress protein chaperoned protein antigen compared with peptide antigen. Journal of Immunology, 184(11), 6309–6319. doi: 10.4049/jimmunol.0903891.Google Scholar
  44. 44.
    Kobayashi, N., Karisola, P., Pena-Cruz, V., Dorfman, D. M., Jinushi, M., Umetsu, S. E., et al. (2007). TIM-1 and TIM-4 glycoproteins bind phosphatidylserine and mediate uptake of apoptotic cells. Immunity, 27(6), 927–940. doi: 10.1016/j.immuni.2007.11.011.PubMedGoogle Scholar
  45. 45.
    Gonzalez, N., Bensinger, S. J., Hong, C., Beceiro, S., Bradley, M. N., Zelcer, N., et al. (2009). Apoptotic cells promote their own clearance and immune tolerance through activation of the nuclear receptor LXR. Immunity, 31(2), 245–258. doi: 10.1016/j.immuni.2009.06.018.Google Scholar
  46. 46.
    Shao, W. H., Zhen, Y., Eisenberg, R. A., & Cohen, P. L. (2009). The Mer receptor tyrosine kinase is expressed on discrete macrophage subpopulations and mainly uses Gas6 as its ligand for uptake of apoptotic cells. Clinical Immunology, 133(1), 138–144. doi: 10.1016/j.clim.2009.06.002.PubMedGoogle Scholar
  47. 47.
    Scott, R. S., McMahon, E. J., Pop, S. M., Reap, E. A., Caricchio, R., Cohen, P. L., et al. (2001). Phagocytosis and clearance of apoptotic cells is mediated by MER. Nature, 411(6834), 207–211. doi: 10.1038/35075603.PubMedGoogle Scholar
  48. 48.
    Jinushi, M., Sato, M., Kanamoto, A., Itoh, A., Nagai, S., Koyasu, S., et al. (2009). Milk fat globule epidermal growth factor-8 blockade triggers tumor destruction through coordinated cell-autonomous and immune-mediated mechanisms. The Journal of Experimental Medicine, 206(6), 1317–1326. doi: 10.1084/jem.20082614.PubMedGoogle Scholar
  49. 49.
    Asano, K., Miwa, M., Miwa, K., Hanayama, R., Nagase, H., Nagata, S., et al. (2004). Masking of phosphatidylserine inhibits apoptotic cell engulfment and induces autoantibody production in mice. The Journal of Experimental Medicine, 200(4), 459–467. doi: 10.1084/jem.20040342.PubMedGoogle Scholar
  50. 50.
    Park, D., Tosello-Trampont, A. C., Elliott, M. R., Lu, M., Haney, L. B., Ma, Z., et al. (2007). BAI1 is an engulfment receptor for apoptotic cells upstream of the ELMO/Dock180/Rac module. Nature, 450(7168), 430–434. doi: 10.1038/nature06329.PubMedGoogle Scholar
  51. 51.
    Jinushi, M., Nakazaki, Y., Dougan, M., Carrasco, D. R., Mihm, M., & Dranoff, G. (2007). MFG-E8-mediated uptake of apoptotic cells by APCs links the pro- and antiinflammatory activities of GM-CSF. Journal of Clinical Investigation, 117(7), 1902–1913. doi: 10.1172/JCI30966.PubMedGoogle Scholar
  52. 52.
    Linger, R. M., Keating, A. K., Earp, H. S., & Graham, D. K. (2008). TAM receptor tyrosine kinases: Biologic functions, signaling, and potential therapeutic targeting in human cancer. Advances in Cancer Research, 100, 35–83. doi: 10.1016/S0065-230X(08)00002-X.PubMedGoogle Scholar
  53. 53.
    Sen, P., Wallet, M. A., Yi, Z., Huang, Y., Henderson, M., Mathews, C. E., et al. (2007). Apoptotic cells induce Mer tyrosine kinase-dependent blockade of NF-kappaB activation in dendritic cells. Blood, 109(2), 653–660. doi: 10.1182/blood-2006-04-017368.PubMedGoogle Scholar
  54. 54.
    Brown, G. D. (2008). Sensing necrosis with Mincle. Nature Immunology, 9(10), 1099–1100. doi: 10.1038/ni1008-1099.PubMedGoogle Scholar
  55. 55.
    Hildner, K., Edelson, B. T., Purtha, W. E., Diamond, M., Matsushita, H., Kohyama, M., et al. (2008). Batf3 deficiency reveals a critical role for CD8alpha+ dendritic cells in cytotoxic T cell immunity. Science, 322(5904), 1097–1100. doi: 10.1126/science.1164206.PubMedGoogle Scholar
  56. 56.
    Dudziak, D., Kamphorst, A. O., Heidkamp, G. F., Buchholz, V. R., Trumpfheller, C., Yamazaki, S., et al. (2007). Differential antigen processing by dendritic cell subsets in vivo. Science, 315(5808), 107–111. doi: 10.1126/science.1136080.PubMedGoogle Scholar
  57. 57.
    Schnorrer, P., Behrens, G. M., Wilson, N. S., Pooley, J. L., Smith, C. M., El-Sukkari, D., et al. (2006). The dominant role of CD8+ dendritic cells in cross-presentation is not dictated by antigen capture. Proceedings of the National Academy of Sciences of the United States of America, 103(28), 10729–10734. doi: 10.1073/pnas.0601956103.PubMedGoogle Scholar
  58. 58.
    McDonnell, A. M., Prosser, A. C., van Bruggen, I., Robinson, B. W., & Currie, A. J. (2010). CD8alpha+ DC are not the sole subset cross-presenting cell-associated tumor antigens from a solid tumor. European Journal of Immunology, 40(6), 1617–1627. doi: 10.1002/eji.200940153.PubMedGoogle Scholar
  59. 59.
    Merad, M., Ginhoux, F., & Collin, M. (2008). Origin, homeostasis and function of Langerhans cells and other Langerin-expressing dendritic cells. Nature Reviews. Immunology, 8(12), 935–947. doi: 10.1038/nri2455.PubMedGoogle Scholar
  60. 60.
    Idoyaga, J., Suda, N., Suda, K., Park, C. G., & Steinman, R. M. (2009). Antibody to Langerin/CD207 localizes large numbers of CD8alpha+ dendritic cells to the marginal zone of mouse spleen. Proceedings of the National Academy of Sciences of the United States of America, 106(5), 1524–1529. doi: 10.1073/pnas.0812247106.PubMedGoogle Scholar
  61. 61.
    Flacher, V., Douillard, P., Ait-Yahia, S., Stoitzner, P., Clair-Moninot, V., Romani, N., et al. (2008). Expression of Langerin/CD207 reveals dendritic cell heterogeneity between inbred mouse strains. Immunology, 123(3), 339–347. doi: 10.1111/j.1365-2567.2007.02785.x.PubMedGoogle Scholar
  62. 62.
    Idoyaga, J., Cheong, C., Suda, K., Suda, N., Kim, J. Y., Lee, H., et al. (2008). Cutting edge: Langerin/CD207 receptor on dendritic cells mediates efficient antigen presentation on MHC I and II products in vivo. Journal of Immunology, 180(6), 3647–3650.Google Scholar
  63. 63.
    Lin, M. L., Zhan, Y., Proietto, A. I., Prato, S., Wu, L., Heath, W. R., et al. (2008). Selective suicide of cross-presenting CD8+ dendritic cells by cytochrome c injection shows functional heterogeneity within this subset. Proceedings of the National Academy of Sciences of the United States of America, 105(8), 3029–3034. doi: 10.1073/pnas.0712394105.PubMedGoogle Scholar
  64. 64.
    Farrand, K. J., Dickgreber, N., Stoitzner, P., Ronchese, F., Petersen, T. R., & Hermans, I. F. (2009). Langerin+ CD8alpha+ dendritic cells are critical for cross-priming and IL-12 production in response to systemic antigens. Journal of Immunology, 183(12), 7732–7742. doi: 10.4049/jimmunol.0902707.Google Scholar
  65. 65.
    Henri, S., Poulin, L. F., Tamoutounour, S., Ardouin, L., Guilliams, M., de Bovis, B., et al. (2010). CD207+ CD103+ dermal dendritic cells cross-present keratinocyte-derived antigens irrespective of the presence of Langerhans cells. The Journal of Experimental Medicine, 207(1), 189–206. doi: 10.1084/jem.20091964.PubMedGoogle Scholar
  66. 66.
    Backer, R., Schwandt, T., Greuter, M., Oosting, M., Jungerkes, F., Tuting, T., et al. (2010). Effective collaboration between marginal metallophilic macrophages and CD8+ dendritic cells in the generation of cytotoxic T cells. Proceedings of the National Academy of Sciences of the United States of America, 107(1), 216–221. doi: 10.1073/pnas.0909541107.PubMedGoogle Scholar
  67. 67.
    Zhang, B. (2008). Targeting the stroma by T cells to limit tumor growth. Cancer Research, 68(23), 9570–9573. doi: 10.1158/0008-5472.CAN-08-2414.PubMedGoogle Scholar
  68. 68.
    Zhang, B., Bowerman, N. A., Salama, J. K., Schmidt, H., Spiotto, M. T., Schietinger, A., et al. (2007). Induced sensitization of tumor stroma leads to eradication of established cancer by T cells. The Journal of Experimental Medicine, 204(1), 49–55. doi: 10.1084/jem.20062056.PubMedGoogle Scholar
  69. 69.
    Schietinger, A., Philip, M., Liu, R. B., Schreiber, K., & Schreiber, H. (2010). Bystander killing of cancer requires the cooperation of CD4+ and CD8+ T cells during the effector phase. Journal of Experimental Medicine, 207, 2469–2477. doi: 10.1084/jem.20092450.PubMedGoogle Scholar
  70. 70.
    Spiotto, M. T., Rowley, D. A., & Schreiber, H. (2004). Bystander elimination of antigen loss variants in established tumors. Natural Medicines, 10(3), 294–298. doi: 10.1038/nm999.Google Scholar
  71. 71.
    Wu, Y., Wu, W., Wong, W. M., Ward, E., Thrasher, A. J., Goldblatt, D., et al. (2009). Human gamma delta T cells: A lymphoid lineage cell capable of professional phagocytosis. Journal of Immunology, 183(9), 5622–5629. doi: 10.4049/jimmunol.0901772.Google Scholar
  72. 72.
    Brandes, M., Willimann, K., Bioley, G., Levy, N., Eberl, M., Luo, M., et al. (2009). Cross-presenting human gammadelta T cells induce robust CD8+ alphabeta T cell responses. Proceedings of the National Academy of Sciences of the United States of America, 106(7), 2307–2312. doi: 10.1073/pnas.0810059106.PubMedGoogle Scholar
  73. 73.
    Melief, C. J. (2008). Cancer immunotherapy by dendritic cells. Immunity, 29(3), 372–383. doi: 10.1016/j.immuni.2008.08.004.PubMedGoogle Scholar
  74. 74.
    Saccheri, F., Pozzi, C., Avogadri, F., Barozzi, S., Faretta, M., Fusi, P., et al. (2010). Bacteria-induced gap junctions in tumors favor antigen cross-presentation and antitumor immunity. Science Translational Medicine, 2(44), 4457. doi: 10.1126/scitranslmed.3000739.Google Scholar
  75. 75.
    de Visser, K. E., Eichten, A., & Coussens, L. M. (2006). Paradoxical roles of the immune system during cancer development. Nature Reviews Cancer, 6(1), 24–37. doi: 10.1038/nrc1782.PubMedGoogle Scholar
  76. 76.
    Lakshmikanth, T., Burke, S., Ali, T. H., Kimpfler, S., Ursini, F., Ruggeri, L., et al. (2009). NCRs and DNAM-1 mediate NK cell recognition and lysis of human and mouse melanoma cell lines in vitro and in vivo. Journal of Clinical Investigation, 119(5), 1251–1263. doi: 10.1172/JCI36022.PubMedGoogle Scholar
  77. 77.
    Chan, C. J., Andrews, D. M., McLaughlin, N. M., Yagita, H., Gilfillan, S., Colonna, M., et al. (2010). DNAM-1/CD155 interactions promote cytokine and NK cell-mediated suppression of poorly immunogenic melanoma metastases. Journal of Immunology, 184(2), 902–911. doi: 10.4049/jimmunol.0903225.Google Scholar
  78. 78.
    Carlsten, M., Baumann, B. C., Simonsson, M., Jadersten, M., Forsblom, A. M., Hammarstedt, C., et al. (2010). Reduced DNAM-1 expression on bone marrow NK cells associated with impaired killing of CD34+ blasts in myelodysplastic syndrome. Leukemia, 24(9), 1607–1616. doi: 10.1038/leu.2010.149.PubMedGoogle Scholar
  79. 79.
    Diefenbach, A., Jensen, E. R., Jamieson, A. M., & Raulet, D. H. (2001). Rae1 and H60 ligands of the NKG2D receptor stimulate tumour immunity. Nature, 413(6852), 165–171. doi: 10.1038/35093109.PubMedGoogle Scholar
  80. 80.
    Soriani, A., Zingoni, A., Cerboni, C., Iannitto, M. L., Ricciardi, M. R., Di Gialleonardo, V., et al. (2009). ATM-ATR-dependent up-regulation of DNAM-1 and NKG2D ligands on multiple myeloma cells by therapeutic agents results in enhanced NK-cell susceptibility and is associated with a senescent phenotype. Blood, 113(15), 3503–3511. doi: 10.1182/blood-2008-08-173914.PubMedGoogle Scholar
  81. 81.
    Kato, N., Tanaka, J., Sugita, J., Toubai, T., Miura, Y., Ibata, M., et al. (2007). Regulation of the expression of MHC class I-related chain A, B (MICA, MICB) via chromatin remodeling and its impact on the susceptibility of leukemic cells to the cytotoxicity of NKG2D-expressing cells. Leukemia, 21(10), 2103–2108. doi: 10.1038/sj.leu.2404862.PubMedGoogle Scholar
  82. 82.
    Schmudde, M., Braun, A., Pende, D., Sonnemann, J., Klier, U., Beck, J. F., et al. (2008). Histone deacetylase inhibitors sensitize tumour cells for cytotoxic effects of natural killer cells. Cancer Letters, 272(1), 110–121. doi: 10.1016/j.canlet.2008.06.027.PubMedGoogle Scholar
  83. 83.
    Fine, J. H., Chen, P., Mesci, A., Allan, D. S., Gasser, S., Raulet, D. H., et al. (2010). Chemotherapy-induced genotoxic stress promotes sensitivity to natural killer cell cytotoxicity by enabling missing-self recognition. Cancer Research, 70(18), 7102–7113. doi: 10.1158/0008-5472.CAN-10-1316.PubMedGoogle Scholar
  84. 84.
    Rey, J., Veuillen, C., Vey, N., Bouabdallah, R., & Olive, D. (2009). Natural killer and gammadelta T cells in haematological malignancies: Enhancing the immune effectors. Trends in Molecular Medicine, 15(6), 275–284. doi: 10.1016/j.molmed.2009.04.005.PubMedGoogle Scholar
  85. 85.
    Pages, F., Galon, J., Dieu-Nosjean, M. C., Tartour, E., Sautes-Fridman, C., & Fridman, W. H. (2010). Immune infiltration in human tumors: A prognostic factor that should not be ignored. Oncogene, 29(8), 1093–1102. doi: 10.1038/onc.2009.416.PubMedGoogle Scholar
  86. 86.
    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. Natural Medicines, 15(10), 1170–1178. doi: 10.1038/nm.2028.Google Scholar
  87. 87.
    Lee, Y., Auh, S. L., Wang, Y., Burnette, B., Meng, Y., Beckett, M., 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. doi: 10.1182/blood-2009-02-206870.PubMedGoogle Scholar
  88. 88.
    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. doi: 10.1158/0008-5472.CAN-09-2982.PubMedGoogle Scholar
  89. 89.
    Johansson, M., Denardo, D. G., & Coussens, L. M. (2008). Polarized immune responses differentially regulate cancer development. Immunological Reviews, 222, 145–154. doi: 10.1111/j.1600-065X.2008.00600.x.PubMedGoogle Scholar
  90. 90.
    DeNardo, D. G., Johansson, M., & Coussens, L. M. (2008). Immune cells as mediators of solid tumor metastasis. Cancer and Metastasis Reviews, 27(1), 11–18. doi: 10.1007/s10555-007-9100-0.PubMedGoogle Scholar
  91. 91.
    Zou, W. (2005). Immunosuppressive networks in the tumour environment and their therapeutic relevance. Nature Reviews Cancer, 5(4), 263–274. doi: 10.1038/nrc1586.PubMedGoogle Scholar
  92. 92.
    Zea, A. H., Rodriguez, P. C., Atkins, M. B., Hernandez, C., Signoretti, S., Zabaleta, J., et al. (2005). Arginase-producing myeloid suppressor cells in renal cell carcinoma patients: A mechanism of tumor evasion. Cancer Research, 65(8), 3044–3048. doi: 10.1158/0008-5472.CAN-04-4505.PubMedGoogle Scholar
  93. 93.
    Serafini, P., De Santo, C., Marigo, I., Cingarlini, S., Dolcetti, L., Gallina, G., et al. (2004). Derangement of immune responses by myeloid suppressor cells. Cancer Immunology, Immunotherapy, 53(2), 64–72. doi: 10.1007/s00262-003-0443-2.PubMedGoogle Scholar
  94. 94.
    Gabrilovich, D. I., & Nagaraj, S. (2009). Myeloid-derived suppressor cells as regulators of the immune system. Nature Reviews Immunology, 9(3), 162–174. doi: 10.1038/nri2506.PubMedGoogle Scholar
  95. 95.
    Chalmin, F., Ladoire, S., Mignot, G., Vincent, J., Bruchard, M., Remy-Martin, J. P., et al. (2010). Membrane-associated Hsp72 from tumor-derived exosomes mediates STAT3-dependent immunosuppressive function of mouse and human myeloid-derived suppressor cells. Journal of Clinical Investigation, 120(2), 457–471. doi: 10.1172/JCI40483.PubMedGoogle Scholar
  96. 96.
    Ostrand-Rosenberg, S. (2010). Myeloid-derived suppressor cells: More mechanisms for inhibiting antitumor immunity. Cancer Immunology Immunotherapy, 59(10), 1593–1600. doi: 10.1007/s00262-010-0855-8.Google Scholar
  97. 97.
    Nagaraj, S., Schrum, A. G., Cho, H. I., Celis, E., & Gabrilovich, D. I. (2010). Mechanism of T cell tolerance induced by myeloid-derived suppressor cells. Journal of Immunology, 184(6), 3106–3116. doi: 10.4049/jimmunol.0902661.Google Scholar
  98. 98.
    Gobert, M., Treilleux, I., Bendriss-Vermare, N., Bachelot, T., Goddard-Leon, S., Arfi, V., et al. (2009). Regulatory T cells recruited through CCL22/CCR4 are selectively activated in lymphoid infiltrates surrounding primary breast tumors and lead to an adverse clinical outcome. Cancer Research, 69(5), 2000–2009. doi: 10.1158/0008-5472.CAN-08-2360.PubMedGoogle Scholar
  99. 99.
    Menetrier-Caux, C., Gobert, M., & Caux, C. (2009). Differences in tumor regulatory T-cell localization and activation status impact patient outcome. Cancer Research, 69(20), 7895–7898. doi: 10.1158/0008-5472.CAN-09-1642.PubMedGoogle Scholar
  100. 100.
    Tan, M. C., Goedegebuure, P. S., Belt, B. A., Flaherty, B., Sankpal, N., Gillanders, W. E., et al. (2009). Disruption of CCR5-dependent homing of regulatory T cells inhibits tumor growth in a murine model of pancreatic cancer. Journal of Immunology, 182(3), 1746–1755.Google Scholar
  101. 101.
    Ramakrishnan, R., Assudani, D., Nagaraj, S., Hunter, T., Cho, H. I., Antonia, S., et al. (2010). Chemotherapy enhances tumor cell susceptibility to CTL-mediated killing during cancer immunotherapy in mice. Journal of Clinical Investigation, 120(4), 1111–1124. doi: 10.1172/JCI40269.PubMedGoogle Scholar
  102. 102.
    Machiels, J. P., Reilly, R. T., Emens, L. A., Ercolini, A. M., Lei, R. Y., Weintraub, D., et al. (2001). Cyclophosphamide, doxorubicin, and paclitaxel enhance the antitumor immune response of granulocyte/macrophage-colony stimulating factor-secreting whole-cell vaccines in HER-2/neu tolerized mice. Cancer Research, 61(9), 3689–3697.PubMedGoogle Scholar
  103. 103.
    Ghiringhelli, F., Larmonier, N., Schmitt, E., Parcellier, A., Cathelin, D., Garrido, C., et al. (2004). CD4+CD25+ regulatory T cells suppress tumor immunity but are sensitive to cyclophosphamide which allows immunotherapy of established tumors to be curative. European Journal of Immunology, 34(2), 336–344. doi: 10.1002/eji.200324181.PubMedGoogle Scholar
  104. 104.
    Roux, S., Apetoh, L., Chalmin, F., Ladoire, S., Mignot, G., Puig, P. E., et al. (2008). CD4+CD25+ Tregs control the TRAIL-dependent cytotoxicity of tumor-infiltrating DCs in rodent models of colon cancer. Journal of Clinical Investigation, 118(11), 3751–3761. doi: 10.1172/JCI35890.PubMedGoogle Scholar
  105. 105.
    Ghiringhelli, F., Menard, C., Puig, P. E., Ladoire, S., Roux, S., Martin, F., et al. (2007). Metronomic cyclophosphamide regimen selectively depletes CD4+CD25+ regulatory T cells and restores T and NK effector functions in end stage cancer patients. Cancer Immunology, Immunotherapy, 56(5), 641–648. doi: 10.1007/s00262-006-0225-8.PubMedGoogle Scholar
  106. 106.
    Markasz, L., Skribek, H., Uhlin, M., Otvos, R., Flaberg, E., Eksborg, S., et al. (2008). Effect of frequently used chemotherapeutic drugs on cytotoxic activity of human cytotoxic T-lymphocytes. Journal of Immunotherapy, 31(3), 283–293. doi: 10.1097/CJI.0b013e3181628b76.PubMedGoogle Scholar
  107. 107.
    Ugel, S., Delpozzo, F., Desantis, G., Papalini, F., Simonato, F., Sonda, N., et al. (2009). Therapeutic targeting of myeloid-derived suppressor cells. Current Opinion in Pharmacology, 9(4), 470–481. doi: 10.1016/j.coph.2009.06.014.PubMedGoogle Scholar
  108. 108.
    Grivennikov, S. I., Greten, F. R., & Karin, M. (2010). Immunity, inflammation, and cancer. Cell, 140(6), 883–899. doi: 10.1016/j.cell.2010.01.025.PubMedGoogle Scholar
  109. 109.
    Luqmani, Y. A. (2005). Mechanisms of drug resistance in cancer chemotherapy. Medical Principles and Practice, 14(Suppl 1), 35–48. doi: 10.1159/000086183.PubMedGoogle Scholar
  110. 110.
    Serrone, L., & Hersey, P. (1999). The chemoresistance of human malignant melanoma: An update. Melanoma Research, 9(1), 51–58.PubMedGoogle Scholar
  111. 111.
    Plati, J., Bucur, O., & Khosravi-Far, R. (2008). Dysregulation of apoptotic signaling in cancer: Molecular mechanisms and therapeutic opportunities. Journal of Cellular Biochemistry, 104(4), 1124–1149. doi: 10.1002/jcb.21707.PubMedGoogle Scholar
  112. 112.
    Trougakos, I. P., Lourda, M., Antonelou, M. H., Kletsas, D., Gorgoulis, V. G., Papassideri, I. S., et al. (2009). Intracellular clusterin inhibits mitochondrial apoptosis by suppressing p53-activating stress signals and stabilizing the cytosolic Ku70-Bax protein complex. Clinical Cancer Research, 15(1), 48–59. doi: 10.1158/1078-0432.CCR-08-1805.PubMedGoogle Scholar
  113. 113.
    Djeu, J. Y., & Wei, S. (2009). Clusterin and chemoresistance. Advances in Cancer Research, 105, 77–92. doi: 10.1016/S0065-230X(09)05005-2.PubMedGoogle Scholar
  114. 114.
    Keating, A. K., Kim, G. K., Jones, A. E., Donson, A. M., Ware, K., Mulcahy, J. M., et al. (2010). Inhibition of Mer and Axl receptor tyrosine kinases in astrocytoma cells leads to increased apoptosis and improved chemosensitivity. Molecular Cancer Therapeutics, 9(5), 1298–1307. doi: 10.1158/1535-7163.MCT-09-0707.PubMedGoogle Scholar
  115. 115.
    Tang, D., Lotze, M. T., Zeh, H. J., & Kang, R. (2010). The redox protein HMGB1 regulates cell death and survival in cancer treatment. Autophagy, 6(8), 1181–1183. doi: 10.4161/auto.6.8.13367.PubMedGoogle Scholar
  116. 116.
    Lin, C. I., Whang, E. E., Abramson, M. A., Donner, D. B., Bertagnolli, M. M., Moore, F. D., Jr., et al. (2009). Galectin-3 regulates apoptosis and doxorubicin chemoresistance in papillary thyroid cancer cells. Biochemical and Biophysical Research Communications, 379(2), 626–631. doi: 10.1016/j.bbrc.2008.12.153.PubMedGoogle Scholar
  117. 117.
    Schonthal, A. H. (2009). Endoplasmic reticulum stress and autophagy as targets for cancer therapy. Cancer Letters, 275(2), 163–169. doi: 10.1016/j.canlet.2008.07.005.PubMedGoogle Scholar
  118. 118.
    Jordan, C. T. (2010). Targeting myeloid leukemia stem cells. Science Translational Medicine, 2(31), 31ps21. doi: 10.1126/scitranslmed.3000914.PubMedGoogle Scholar
  119. 119.
    LaBarge, M. A. (2010). The difficulty of targeting cancer stem cell niches. Clinical Cancer Research, 16(12), 3121–3129. doi: 10.1158/1078-0432.CCR-09-2933.PubMedGoogle Scholar
  120. 120.
    Speiser, D. E., & Romero, P. (2010). Molecularly defined vaccines for cancer immunotherapy, and protective T cell immunity. Seminars in Immunology, 22(3), 144–154. doi: 10.1016/j.smim.2010.03.004.PubMedGoogle Scholar
  121. 121.
    Dubensky, T. W., Jr., & Reed, S. G. (2010). Adjuvants for cancer vaccines. Seminars in Immunology, 22(3), 155–161. doi: 10.1016/j.smim.2010.04.007.PubMedGoogle Scholar
  122. 122.
    Palucka, K., Ueno, H., Zurawski, G., Fay, J., & Banchereau, J. (2010). Building on dendritic cell subsets to improve cancer vaccines. Current Opinion in Immunology, 22(2), 258–263. doi: 10.1016/j.coi.2010.02.010.PubMedGoogle Scholar
  123. 123.
    Palucka, A. K., Ueno, H., Fay, J. W., & Banchereau, J. (2007). Taming cancer by inducing immunity via dendritic cells. Immunological Reviews, 220, 129–150. doi: 10.1111/j.1600-065X.2007.00575.x.PubMedGoogle Scholar
  124. 124.
    Chamoto, K., Takeshima, T., Wakita, D., Ohkuri, T., Ashino, S., Omatsu, T., et al. (2009). Combination immunotherapy with radiation and CpG-based tumor vaccination for the eradication of radio- and immuno-resistant lung carcinoma cells. Cancer Science, 100(5), 934–939. doi: 10.1111/j.1349-7006.2009.01114.x.PubMedGoogle Scholar
  125. 125.
    Conforti, R., Ma, Y., Morel, Y., Paturel, C., Terme, M., Viaud, S., et al. (2010). Opposing effects of Toll-like receptor (TLR3) signaling in tumors can be therapeutically uncoupled to optimize the anticancer efficacy of TLR3 ligands. Cancer Research, 70(2), 490–500. doi: 10.1158/0008-5472.CAN-09-1890.PubMedGoogle Scholar
  126. 126.
    Sharma, M. D., Baban, B., Chandler, P., Hou, D. Y., Singh, N., Yagita, H., et al. (2007). Plasmacytoid dendritic cells from mouse tumor-draining lymph nodes directly activate mature Tregs via indoleamine 2,3-dioxygenase. Journal of Clinical Investigation, 117(9), 2570–2582. doi: 10.1172/JCI31911.PubMedGoogle Scholar
  127. 127.
    Ou, X., Cai, S., Liu, P., Zeng, J., He, Y., Wu, X., et al. (2008). Enhancement of dendritic cell-tumor fusion vaccine potency by indoleamine-pyrrole 2,3-dioxygenase inhibitor, 1-MT. Journal of Cancer Research and Clinical Oncology, 134(5), 525–533. doi: 10.1007/s00432-007-0315-9.PubMedGoogle Scholar
  128. 128.
    Herrmann, A., Kortylewski, M., Kujawski, M., Zhang, C., Reckamp, K., Armstrong, B., et al. (2010). Targeting Stat3 in the myeloid compartment drastically improves the in vivo antitumor functions of adoptively transferred T cells. Cancer Research, 70(19), 7455–7464. doi: 10.1158/0008-5472.CAN-10-0736.PubMedGoogle Scholar
  129. 129.
    Nam, J. S., Terabe, M., Mamura, M., Kang, M. J., Chae, H., Stuelten, C., et al. (2008). An anti-transforming growth factor beta antibody suppresses metastasis via cooperative effects on multiple cell compartments. Cancer Research, 68(10), 3835–3843. doi: 10.1158/0008-5472.CAN-08-0215.PubMedGoogle Scholar
  130. 130.
    Wang, L., Yi, T., Kortylewski, M., Pardoll, D. M., Zeng, D., & Yu, H. (2009). IL-17 can promote tumor growth through an IL-6-Stat3 signaling pathway. The Journal of Experimental Medicine, 206(7), 1457–1464. doi: 10.1084/jem.20090207.PubMedGoogle Scholar
  131. 131.
    Yoshio-Hoshino, N., Adachi, Y., Aoki, C., Pereboev, A., Curiel, D. T., & Nishimoto, N. (2007). Establishment of a new interleukin-6 (IL-6) receptor inhibitor applicable to the gene therapy for IL-6-dependent tumor. Cancer Research, 67(3), 871–875. doi: 10.1158/0008-5472.CAN-06-3641.PubMedGoogle Scholar
  132. 132.
    Shinriki, S., Jono, H., Ota, K., Ueda, M., Kudo, M., Ota, T., et al. (2009). Humanized anti-interleukin-6 receptor antibody suppresses tumor angiogenesis and in vivo growth of human oral squamous cell carcinoma. Clinical Cancer Research, 15(17), 5426–5434. doi: 10.1158/1078-0432.CCR-09-0287.PubMedGoogle Scholar
  133. 133.
    Matsuzaki, J., Gnjatic, S., Mhawech-Fauceglia, P., Beck, A., Miller, A., Tsuji, T., et al. (2010). Tumor-infiltrating NY-ESO-1-specific CD8+ T cells are negatively regulated by LAG-3 and PD-1 in human ovarian cancer. Proceedings of the National Academy of Sciences of the United States of America, 107(17), 7875–7880. doi: 10.1073/pnas.1003345107.PubMedGoogle Scholar
  134. 134.
    Jin, H. T., Anderson, A. C., Tan, W. G., West, E. E., Ha, S. J., Araki, K., et al. (2010). Cooperation of Tim-3 and PD-1 in CD8 T-cell exhaustion during chronic viral infection. Proceedings of the National Academy of Sciences of the United States of America, 107(33), 14733–14738. doi: 10.1073/pnas.1009731107.PubMedGoogle Scholar
  135. 135.
    Fourcade, J., Sun, Z., Benallaoua, M., Guillaume, P., Luescher, I. F., Sander, C., et al. (2010). Upregulation of Tim-3 and PD-1 expression is associated with tumor antigen-specific CD8+ T cell dysfunction in melanoma patients. The Journal of Experimental Medicine, 207(10), 2175–2186. doi: 10.1084/jem.20100637.PubMedGoogle Scholar
  136. 136.
    Sakuishi, K., Apetoh, L., Sullivan, J. M., Blazar, B. R., Kuchroo, V. K., & Anderson, A. C. (2010). Targeting Tim-3 and PD-1 pathways to reverse T cell exhaustion and restore anti-tumor immunity. The Journal of Experimental Medicine, 207(10), 2187–2194. doi: 10.1084/jem.20100643.PubMedGoogle Scholar
  137. 137.
    Derre, L., Rivals, J. P., Jandus, C., Pastor, S., Rimoldi, D., Romero, P., et al. (2010). BTLA mediates inhibition of human tumor-specific CD8+ T cells that can be partially reversed by vaccination. Journal of Clinical Investigation, 120(1), 157–167. doi: 10.1172/JCI40070.PubMedGoogle Scholar
  138. 138.
    Robert, C., & Ghiringhelli, F. (2009). What is the role of cytotoxic T lymphocyte-associated antigen 4 blockade in patients with metastatic melanoma? The Oncologist, 14(8), 848–861. doi: 10.1634/theoncologist.2009-0028.PubMedGoogle Scholar
  139. 139.
    Peggs, K. S., Quezada, S. A., Chambers, C. A., Korman, A. J., & Allison, J. P. (2009). Blockade of CTLA-4 on both effector and regulatory T cell compartments contributes to the antitumor activity of anti-CTLA-4 antibodies. The Journal of Experimental Medicine, 206(8), 1717–1725. doi: 10.1084/jem.20082492.PubMedGoogle Scholar
  140. 140.
    Chen, H., Liakou, C. I., Kamat, A., Pettaway, C., Ward, J. F., Tang, D. N., et al. (2009). Anti-CTLA-4 therapy results in higher CD4+ICOShi T cell frequency and IFN-gamma levels in both nonmalignant and malignant prostate tissues. Proceedings of the National Academy of Sciences of the United States of America, 106(8), 2729–2734. doi: 10.1073/pnas.0813175106.PubMedGoogle Scholar
  141. 141.
    Curran, M. A., Montalvo, W., Yagita, H., & Allison, J. P. (2010). PD-1 and CTLA-4 combination blockade expands infiltrating T cells and reduces regulatory T and myeloid cells within B16 melanoma tumors. Proceedings of the National Academy of Sciences of the United States of America, 107(9), 4275–4280. doi: 10.1073/pnas.0915174107.PubMedGoogle Scholar
  142. 142.
    Westwood, J. A., Darcy, P. K., Guru, P. M., Sharkey, J., Pegram, H. J., Amos, S. M., et al. (2010). Three agonist antibodies in combination with high-dose IL-2 eradicate orthotopic kidney cancer in mice. Journal of Translational Medicine, 8, 42. doi: 10.1186/1479-5876-8-42.PubMedGoogle Scholar
  143. 143.
    Dudley, M. E., Yang, J. C., Sherry, R., Hughes, M. S., Royal, R., Kammula, U., et al. (2008). Adoptive cell therapy for patients with metastatic melanoma: Evaluation of intensive myeloablative chemoradiation preparative regimens. Journal of Clinical Oncology, 26(32), 5233–5239. doi: 10.1200/JCO.2008.16.5449.PubMedGoogle Scholar
  144. 144.
    Quezada, S. A., Simpson, T. R., Peggs, K. S., Merghoub, T., Vider, J., Fan, X., et al. (2010). Tumor-reactive CD4(+) T cells develop cytotoxic activity and eradicate large established melanoma after transfer into lymphopenic hosts. The Journal of Experimental Medicine, 207(3), 637–650. doi: 10.1084/jem.20091918.PubMedGoogle Scholar
  145. 145.
    Garcia-Hernandez Mde, L., Hamada, H., Reome, J. B., Misra, S. K., Tighe, M. P., & Dutton, R. W. (2010). Adoptive transfer of tumor-specific Tc17 effector T cells controls the growth of B16 melanoma in mice. Journal of Immunology, 184(8), 4215–4227. doi: 10.4049/jimmunol.0902995.Google Scholar
  146. 146.
    Muranski, P., Boni, A., Antony, P. A., Cassard, L., Irvine, K. R., Kaiser, A., et al. (2008). Tumor-specific Th17-polarized cells eradicate large established melanoma. Blood, 112(2), 362–373. doi: 10.1182/blood-2007-11-120998.PubMedGoogle Scholar
  147. 147.
    Miller, J. S., Soignier, Y., Panoskaltsis-Mortari, A., McNearney, S. A., Yun, G. H., Fautsch, S. K., et al. (2005). Successful adoptive transfer and in vivo expansion of human haploidentical NK cells in patients with cancer. Blood, 105(8), 3051–3057. doi: 10.1182/blood-2004-07-2974.PubMedGoogle Scholar
  148. 148.
    Pegram, H. J., Jackson, J. T., Smyth, M. J., Kershaw, M. H., & Darcy, P. K. (2008). Adoptive transfer of gene-modified primary NK cells can specifically inhibit tumor progression in vivo. Journal of Immunology, 181(5), 3449–3455.Google Scholar

Copyright information

© Springer Science+Business Media, LLC 2011

Authors and Affiliations

  • Yuting Ma
    • 1
    • 2
    • 3
  • Rosa Conforti
    • 1
    • 2
    • 3
  • Laetitia Aymeric
    • 1
    • 2
    • 3
  • Clara Locher
    • 1
    • 2
    • 3
  • Oliver Kepp
    • 4
    • 5
  • Guido Kroemer
    • 4
    • 5
    • 6
    • 7
    • 9
  • Laurence Zitvogel
    • 1
    • 2
    • 3
    • 8
  1. 1.INSERM, U1015VillejuifFrance
  2. 2.Institut Gustave RoussyVillejuifFrance
  3. 3.Université Paris-SudVillejuifFrance
  4. 4.INSERM U848VillejuifFrance
  5. 5.Metabolomics Platform, Institut Gustave RoussyVillejuifFrance
  6. 6.Pôle de Biologie, Hôpital Européen Georges Pompidou, AP-HPParisFrance
  7. 7.Université Paris DescartesParisFrance
  8. 8.CICBT507, Institut Gustave RoussyVillejuifFrance
  9. 9.Centre de Recherche des CordeliersParisFrance

Personalised recommendations