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Accumulation of Activated Invariant Natural Killer T Cells in the Tumor Microenvironment after α-Galactosylceramide-Pulsed Antigen Presenting Cells

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Abstract

Purpose

The intravenous administration of α-Galactosylceramide (α-GalCer)-pulsed antigen presenting cells (APCs) is well tolerated and the increased IFN-γ producing cells in the peripheral blood after the treatment appeared to be associated with prolonged survival. An exploratory study protocol was designed with the preoperative administration of α-GalCer-pulsed APCs to clarify the mechanisms of these findings, while especially focusing on the precise tumor site.

Methods

Patients with operable advanced lung cancer received an intravenous injection of α-GalCer-pulsed APCs before surgery. The resected lung and tumor infiltrating lymphocytes (TILs) as well as peripheral blood mononuclear cells were collected and the invariant NKT (iNKT) cell-specific immune responses were analyzed.

Results

Four patients completed the study protocol. We observed a significant increase in iNKT cell numbers in the TILs and augmented IFN-γ production by the α-GalCer-stimulated TILs.

Conclusion

The administration of α-GalCer-pulsed APCs successfully induced the dramatic infiltration and activation of iNKT cells in the tumor microenvironment.

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References

  1. Kawano T, Cui J, Koezuka Y, Toura I, Kaneko Y, Motoki K, et al. CD1d-restricted and TCR-mediated activation of Vα14 NKT cells by glycosylceramides. Science. 1997;278:1626–9.

    Article  PubMed  CAS  Google Scholar 

  2. Brossay L, Chioda M, Burdin N, Koezuka Y, Casorati G, Dellabona P, et al. CD1d-mediated recognition of an α-galactosylceramide by natural killer T cells is highly conserved through mammalian evolution. J Exp Med. 1998;188:1521–8.

    Article  PubMed  CAS  Google Scholar 

  3. Spada FM, Koezuka Y, Porcelli SA. CD1d-restricted recognition of synthetic glycolipid antigens by human natural killer T cells. J Exp Med. 1998;188:1529–34.

    Article  PubMed  CAS  Google Scholar 

  4. Tahir SM, Cheng O, Shaulov A, Koezuka Y, Bubley GJ, Wilson SB, et al. Loss of IFN-γ production by invariant NK T cells in advanced cancer. J Immunol. 2001;167:4046–50.

    PubMed  CAS  Google Scholar 

  5. Motohashi S, Kobayashi S, Ito T, Magara KK, Mikuni O, Kamada N, et al. Preserved IFN-γ production of circulating Vα24 NKT cells in primary lung cancer patients. Int J Cancer. 2002;102:159–65.

    Article  PubMed  CAS  Google Scholar 

  6. Molling JW, Kolgen W, van der Vliet HJ, Boomsma MF, Kruizenga H, Smorenburg CH, et al. Peripheral blood IFN-g-secreting Vα24+Vβ11+ NKT cell numbers are decreased in cancer patients independent of tumor type or tumor load. Int J Cancer. 2005;116:87–93.

    Article  PubMed  CAS  Google Scholar 

  7. van der Vliet HJ, Nishi N, Koezuka Y, von Blomberg BM, van den Eertwegh AJ, Porcelli SA, et al. Potent expansion of human natural killer T cells using α-galactosylceramide (KRN7000)-loaded monocyte-derived dendritic cells, cultured in the presence of IL-7 and IL-15. J Immunol Methods. 2001;247:61–72.

    Article  PubMed  Google Scholar 

  8. Yanagisawa K, Seino K, Ishikawa Y, Nozue M, Todoroki T, Fukao K. Impaired proliferative response of Vα24 NKT cells from cancer patients against α-galactosylceramide. J Immunol. 2002;168:6494–9.

    PubMed  CAS  Google Scholar 

  9. Dhodapkar MV, Geller MD, Chang DH, Shimizu K, Fujii S, Dhodapkar KM, et al. A reversible defect in natural killer T cell function characterizes the progression of premalignant to malignant multiple myeloma. J Exp Med. 2003;197:1667–76.

    Article  PubMed  CAS  Google Scholar 

  10. Molling JW, Langius JA, Langendijk JA, Leemans CR, Bontkes HJ, van der Vliet HJ, et al. Low levels of circulating invariant natural killer T cells predict poor clinical outcome in patients with head and neck squamous cell carcinoma. J Clin Oncol. 2007;25:862–8.

    Article  PubMed  Google Scholar 

  11. Ishikawa A, Motohashi S, Ishikawa E, Fuchida H, Higashino K, Otsuji M, et al. A phase I study of α-galactosylceramide (KRN7000)-pulsed dendritic cells in patients with advanced and recurrent non-small cell lung cancer. Clin Cancer Res. 2005;11:1910–7.

    Article  PubMed  CAS  Google Scholar 

  12. Motohashi S, Ishikawa A, Ishikawa E, Otsuji M, Iizasa T, Hanaoka H, et al. A phase I study of in vitro expanded natural killer T cells in patients with advanced and recurrent non-small cell lung cancer. Clin Cancer Res. 2006;12:6079–86.

    Article  PubMed  CAS  Google Scholar 

  13. Motohashi S, Nagato K, Kunii N, Yamamoto H, Yamasaki K, Okita K, et al. A phase I-II study of α-galactosylceramide-pulsed IL-2/GM-CSF-cultured peripheral blood mononuclear cells in patients with advanced and recurrent non-small cell lung cancer. J Immunol. 2009;182:2492–501.

    Article  PubMed  CAS  Google Scholar 

  14. Motohashi S, Nakayama T. Invariant natural killer T cell-based immunotherapy for cancer. Immunotherapy. 2009;1:73–82.

    Article  PubMed  CAS  Google Scholar 

  15. Ishikawa E, Motohashi S, Ishikawa A, Ito T, Uchida T, Kaneko T, et al. Dendritic cell maturation by CD11c- T cells and Vα24+ natural killer T-cell activation by α-galactosylceramide. Int J Cancer. 2005;117:265–73.

    Article  PubMed  CAS  Google Scholar 

  16. Grabenbauer GG, Lahmer G, Distel L, Niedobitek G. Tumor-infiltrating cytotoxic T cells but not regulatory T cells predict outcome in anal squamous cell carcinoma. Clin Cancer Res. 2006;12:3355–60.

    Article  PubMed  CAS  Google Scholar 

  17. van Beek J, zur Hausen A, Snel SN, Berkhof J, Kranenbarg EK, van de Velde CJ, et al. Morphological evidence of an activated cytotoxic T-cell infiltrate in EBV-positive gastric carcinoma preventing lymph node metastases. Am J Surg Pathol. 2006;30:59–65.

    Article  PubMed  Google Scholar 

  18. Schumacher K, Haensch W, Roefzaad C, Schlag PM. Prognostic significance of activated CD8(+) T cell infiltrations within esophageal carcinomas. Cancer Res. 2001;61:3932–6.

    PubMed  CAS  Google Scholar 

  19. Cho Y, Miyamoto M, Kato K, Fukunaga A, Shichinohe T, Kawarada Y, et al. CD4+ and CD8+ T cells cooperate to improve prognosis of patients with esophageal squamous cell carcinoma. Cancer Res. 2003;63:1555–9.

    PubMed  CAS  Google Scholar 

  20. Menon AG, Janssen-van Rhijn CM, Morreau H, Putter H, Tollenaar RA, van de Velde CJ, et al. Immune system and prognosis in colorectal cancer: a detailed immunohistochemical analysis. Lab Invest. 2004;84:493–501.

    Article  PubMed  CAS  Google Scholar 

  21. Prall F, Duhrkop T, Weirich V, Ostwald C, Lenz P, Nizze H, et al. Prognostic role of CD8+ tumor-infiltrating lymphocytes in stage III colorectal cancer with and without microsatellite instability. Hum Pathol. 2004;35:808–16.

    Article  PubMed  CAS  Google Scholar 

  22. Zhang L, Conejo-Garcia JR, Katsaros D, Gimotty PA, Massobrio M, Regnani G, et al. Intratumoral T cells, recurrence, and survival in epithelial ovarian cancer. N Engl J Med. 2003;348:203–13.

    Article  PubMed  CAS  Google Scholar 

  23. Ryschich E, Notzel T, Hinz U, Autschbach F, Ferguson J, Simon I, et al. Control of T-cell-mediated immune response by HLA class I in human pancreatic carcinoma. Clin Cancer Res. 2005;11:498–504.

    PubMed  CAS  Google Scholar 

  24. Sato E, Olson SH, Ahn J, Bundy B, Nishikawa H, Qian F, et al. Intraepithelial CD8+ tumor-infiltrating lymphocytes and a high CD8+/regulatory T cell ratio are associated with favorable prognosis in ovarian cancer. Proc Natl Acad Sci U S A. 2005;102:18538–43.

    Article  PubMed  CAS  Google Scholar 

  25. Curiel TJ, Coukos G, Zou L, Alvarez X, Cheng P, Mottram P, et al. Specific recruitment of regulatory T cells in ovarian carcinoma fosters immune privilege and predicts reduced survival. Nat Med. 2004;10:942–9.

    Article  PubMed  CAS  Google Scholar 

  26. Alvaro T, Lejeune M, Salvado MT, Bosch R, Garcia JF, Jaen J, et al. Outcome in Hodgkin’s lymphoma can be predicted from the presence of accompanying cytotoxic and regulatory T cells. Clin Cancer Res. 2005;11:1467–73.

    Article  PubMed  Google Scholar 

  27. Gao Q, Qiu SJ, Fan J, Zhou J, Wang XY, **ao YS, et al. Intratumoral balance of regulatory and cytotoxic T cells is associated with prognosis of hepatocellular carcinoma after resection. J Clin Oncol. 2007;25:2586–93.

    Article  PubMed  Google Scholar 

  28. Tachibana T, Onodera H, Tsuruyama T, Mori A, Nagayama S, Hiai H, et al. Increased intratumor Vα24-positive natural killer T cells: a prognostic factor for primary colorectal carcinomas. Clin Cancer Res. 2005;11:7322–7.

    Article  PubMed  CAS  Google Scholar 

  29. Sawabata N, Miyaoka E, Asamura H, Nakanishi Y, Eguchi K, Mori M, et al. Japanese lung cancer registry study of 11,663 surgical cases in 2004: demographic and prognosis changes over decade. J Thorac Oncol. 2011;6:1229–35.

    Article  PubMed  Google Scholar 

  30. Arriagada R, Bergman B, Dunant A, Le Chevalier T, Pignon JP, Vansteenkiste J. Cisplatin-based adjuvant chemotherapy in patients with completely resected non-small-cell lung cancer. N Engl J Med. 2004;350:351–60.

    Article  PubMed  Google Scholar 

  31. Winton T, Livingston R, Johnson D, Rigas J, Johnston M, Butts C, et al. Vinorelbine plus cisplatin vs. observation in resected non-small-cell lung cancer. N Engl J Med. 2005;352:2589–97.

    Article  PubMed  CAS  Google Scholar 

  32. Douillard JY, Rosell R, De Lena M, Carpagnano F, Ramlau R, Gonzales-Larriba JL, et al. Adjuvant vinorelbine plus cisplatin versus observation in patients with completely resected stage IB-IIIA non-small-cell lung cancer (Adjuvant Navelbine International Trialist Association [ANITA]): a randomised controlled trial. Lancet Oncol. 2006;7:719–27.

    Article  PubMed  CAS  Google Scholar 

  33. Pignon JP, Tribodet H, Scagliotti GV, Douillard JY, Shepherd FA, Stephens RJ, et al. Lung adjuvant cisplatin evaluation: a pooled analysis by the LACE Collaborative Group. J Clin Oncol. 2008;26:3552–9.

    Article  PubMed  Google Scholar 

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Acknowledgements

We thank Kyowa Hakko Kirin Co. Ltd. for providing clinical grade α-GalCer (KRN7000) for these studies. We also thank all the nurses and staff surgeons in the Department of the Thoracic Surgery, Chiba University Hospital, Chiba, Japan, for their excellent help with patient care and continuous support.

This work was supported by Global COE Program (Global Center for Education and Research in Immune System Regulation and Treatment), City Area Program (Kazusa ⁄ Chiba Area) MEXT (Japan), and by grants from the Ministry of Education, Culture, Sports, Science and Technology (Japan) (Grants-in-Aid: for Scientific Research on Priority Areas #17016010; Scientific Research [B] #21390147, and Scientific Research [C] #21591808, and Cancer Translational Research Project), the Ministry of Health, Labor and Welfare (Japan), Uehara Memorial Foundation, Mochida Foundation, Chiba Foundation for Health Promotion and Disease Prevention and Mitsui Life Social Welfare Foundation.

Conflict of interest

The authors declare that they have no conflict of interest.

Author information

Authors and Affiliations

  1. Department of Immunology, Graduate School of Medicine, Chiba University, Clinical Research Center, Chiba University Hospital, 1-8-1 Inohana, Chuo-ku, Chiba, 260-8670, Japan

    Kaoru Nagato, Shinichiro Motohashi, Fumihiro Ishibashi, Kohsuke Okita, Kazuki Yamasaki & Toshinori Nakayama

  2. General Thoracic Surgery, Graduate School of Medicine, Chiba University, Clinical Research Center, Chiba University Hospital, 1-8-1 Inohana, Chuo-ku, Chiba, 260-8670, Japan

    Kaoru Nagato, Shinichiro Motohashi, Fumihiro Ishibashi, Yasumitsu Moriya, Hidehisa Hoshino, Shigetoshi Yoshida & Ichiro Yoshino

  3. Graduate School of Medicine, Chiba University, Clinical Research Center, Chiba University Hospital, 1-8-1 Inohana, Chuo-ku, Chiba, 260-8670, Japan

    Hideki Hanaoka

  4. Research Unit for Cellular Immunotherapy, RIKEN Research Center for Allergy and Immunology, 1-7-22, Suehiro-cho, Tsurumi-ku, Yokohama, Japan

    Shin-ichiro Fujii

  5. Laboratory for Immune Regulation, RIKEN Research Center for Allergy and Immunology, 1-7-22, Suehiro-cho, Tsurumi-ku, Yokohama, Japan

    Masaru Taniguchi

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  1. Kaoru Nagato
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Correspondence to Shinichiro Motohashi.

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Nagato, K., Motohashi, S., Ishibashi, F. et al. Accumulation of Activated Invariant Natural Killer T Cells in the Tumor Microenvironment after α-Galactosylceramide-Pulsed Antigen Presenting Cells. J Clin Immunol 32, 1071–1081 (2012). https://doi.org/10.1007/s10875-012-9697-9

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  • DOI: https://doi.org/10.1007/s10875-012-9697-9

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