Artificial thymic organoid culture generates functional iPSC-derived CD4+ invariant natural killer T cells

1. Zitvogel, L., Tesniere, A. & Kroemer, G. Cancer despite immunosurveillance: immunoselection and immunosubversion. Nat. Rev. Immunol. 6, 715–727 (2006).

   Google Scholar 

2. Brennan, P. J., Brigl, M. & Brenner, M. B. Invariant natural killer T cells: an innate activation scheme linked to diverse effector functions. Nat. Rev. Immunol. 13, 101–117 (2013).

   Google Scholar 

3. Liu, T.-Y. et al. Distinct subsets of human invariant NKT cells differentially regulate T helper responses via dendritic cells. Eur. J. Immunol. 38, 1012–1023 (2008).

   Google Scholar 

4. Metelitsa, L. S. et al. Human NKT cells mediate antitumor cytotoxicity directly by recognizing target cell CD1d with bound ligand or indirectly by producing IL-2 to activate NK cells. J. Immunol. 167, 3114–3122 (2001).

   Google Scholar 

5. Hong, C. et al. Regulation of secondary antigen-specific CD8(+) T-cell responses by natural killer T cells. Cancer Res. 69, 4301–4308 (2009).

   Google Scholar 

6. Motohashi, S. et al. A phase I-II study of alpha-galactosylceramide-pulsed IL-2/GM-CSF-cultured peripheral blood mononuclear cells in patients with advanced and recurrent non-small cell lung cancer. J. Immunol. 182, 2492–2501 (2009).

   Google Scholar 

7. Yamasaki, K. et al. Induction of NKT cell-specific immune responses in cancer tissues after NKT cell-targeted adoptive immunotherapy. Clin. Immunol. 138, 255–265 (2011).

   Google Scholar 

8. Tachibana, T. et al. Increased intratumor Valpha24-positive natural killer T cells: a prognostic factor for primary colorectal carcinomas. Clin. Cancer Res. 11, 7322–7327 (2005).

   Google Scholar 

9. Song, L. et al. Oncogene MYCN regulates localization of NKT cells to the site of disease in neuroblastoma. J. Clin. Investig. 117, 2702–2712 (2007).

   Google Scholar 

10. Berzins, S. P., Smyth, M. J. & Baxter, A. G. Presumed guilty: natural killer T cell defects and human disease. Nat. Rev. Immunol. 11, 131–142 (2011).

    Google Scholar 

11. Salio, M., Silk, J. D., Jones, E. Y. & Cerundolo, V. Biology of CD1- and MR1-restricted T cells. Annu. Rev. Immunol. 32, 323–366 (2014).

    Google Scholar 

12. Kitayama, S. et al. Cellular adjuvant properties, direct cytotoxicity of re-differentiated Vα24 invariant NKT-like cells from human induced pluripotent stem cells. Stem Cell Rep. 6, 213–227 (2016).

    Google Scholar 

13. Yamada, D. et al. Efficient regeneration of human Vα24+ invariant natural killer T cells and their anti-tumor activity in vivo. Stem Cells 34, 2852–2860 (2016).

    Google Scholar 

14. Phetfong, J. et al. Cell type of origin influences iPSC generation and differentiation to cells of the hematoendothelial lineage. Cell Tissue Res. 365, 101–112 (2016).

    Google Scholar 

15. Nishizawa, M. et al. Epigenetic variation between human induced pluripotent stem cell lines is an indicator of differentiation capacity. Cell Stem Cell 19, 341–354 (2016).

    Google Scholar 

16. Nishimura, T. et al. Generation of rejuvenated antigen-specific T cells by reprogramming to pluripotency and redifferentiation. Cell Stem Cell 12, 114–126 (2013).

    Google Scholar 

17. Seet, C. S. et al. Generation of mature T cells from human hematopoietic stem and progenitor cells in artificial thymic organoids. Nat. Methods 14, 521–530 (2017).

    Google Scholar 

18. Montel-Hagen, A. et al. Organoid-induced differentiation of conventional T cells from human pluripotent stem cells. Cell Stem Cell 24, 376–389.e8 (2019).

    Google Scholar 

19. Iriguchi, S. et al. A clinically applicable and scalable method to regenerate T-cells from iPSCs for off-the-shelf T-cell immunotherapy. Nat. Commun. 12, 430 (2021).

    Google Scholar 

20. Kawano, T. et al. CD1d-restricted and TCR-mediated activation of valpha14 NKT cells by glycosylceramides. Science 278, 1626–1629 (1997).

    Google Scholar 

21. Lee, P. T., Benlagha, K., Teyton, L. & Bendelac, A. Distinct functional lineages of human V(alpha)24 natural killer T cells. J. Exp. Med. 195, 637–641 (2002).

    Google Scholar 

22. Gumperz, J. E., Miyake, S., Yamamura, T. & Brenner, M. B. Functionally distinct subsets of CD1d-restricted natural killer T cells revealed by CD1d tetramer staining. J. Exp. Med. 195, 625–636 (2002).

    Google Scholar 

23. Kim, C. H., Johnston, B. & Butcher, E. C. Trafficking machinery of NKT cells: shared and differential chemokine receptor expression among V alpha 24(+)V beta 11(+) NKT cell subsets with distinct cytokine-producing capacity. Blood 100, 11–16 (2002).

    Google Scholar 

24. Kuylenstierna, C. et al. NKG2D performs two functions in invariant NKT cells: direct TCR-independent activation of NK-like cytolysis and co-stimulation of activation by CD1d. Eur. J. Immunol. 41, 1913–1923 (2011).

    Google Scholar 

25. Trinchieri, G. Interleukin-12 and the regulation of innate resistance and adaptive immunity. Nat. Rev. Immunol. 3, 133–146 (2003).

    Google Scholar 

26. Takeya, M. & Komohara, Y. Role of tumor-associated macrophages in human malignancies: friend or foe? Pathol. Int. 66, 491–505 (2016).

    Google Scholar 

27. Song, L. et al. Valpha24-invariant NKT cells mediate antitumor activity via killing of tumor-associated macrophages. J. Clin. Investig. 119, 1524–1536 (2009).

    Google Scholar 

28. Godfrey, D. I., Stankovic, S. & Baxter, A. G. Raising the NKT cell family. Nat. Immunol. 11, 197–206 (2010).

    Google Scholar 

29. Veillette, A., Dong, Z. & Latour, S. Consequence of the SLAM-SAP signaling pathway in innate-like and conventional lymphocytes. Immunity 27, 698–710 (2007).

    Google Scholar 

30. Griewank, K. et al. Homotypic interactions mediated by Slamf1 and Slamf6 receptors control NKT cell lineage development. Immunity 27, 751–762 (2007).

    Google Scholar 

31. Borowski, C. & Bendelac, A. Signaling for NKT cell development: the SAP-FynT connection. J. Exp. Med. 201, 833–836 (2005).

    Google Scholar 

32. Chang, D. H. et al. Sustained expansion of NKT cells and antigen-specific T cells after injection of alpha-galactosyl-ceramide loaded mature dendritic cells in cancer patients. J. Exp. Med. 201, 1503–1517 (2005).

    Google Scholar 

33. Li, Y.-R. et al. Development of allogeneic HSC-engineered iNKT cells for off-the-shelf cancer immunotherapy. Cell Rep. Med. 2, 100449 (2021).

    Google Scholar 

34. Bonecchi, R., Locati, M. & Mantovani, A. Chemokines and cancer: a fatal attraction. Cancer Cell 19, 434–435 (2011).

    Google Scholar 

35. van der Vliet, H. J. J. et al. Polarization of Valpha24+ Vbeta11+ natural killer T cells of healthy volunteers and cancer patients using alpha-galactosylceramide-loaded and environmentally instructed dendritic cells. Cancer Res. 63, 4101–4106 (2003).

    Google Scholar 

36. Hase, K. et al. Macrophage-like iPS-derived Suppressor Cells Reduce Th1-mediated Immune Response to a Retinal Antigen. Curr. Eye Res. 46, 1908–1916 (2021).

    Google Scholar 

37. Nakagawa, M. et al. A novel efficient feeder-free culture system for the derivation of human induced pluripotent stem cells. Sci. Rep. 4, 3594 (2014).

    Google Scholar 

38. Itoh, K. et al. Reproducible establishment of hemopoietic supportive stromal cell lines from murine bone marrow. Exp. Hematol. 17, 145–153 (1989).

    Google Scholar 

Download references

Authors and Affiliations

1. Department of Cell Growth and Differentiation, Shin Kaneko Laboratory, Center for iPS Cell Research and Application (CiRA), Kyoto University, Kyoto, Japan

   Sara Shiina, Tatsuki Ueda, Shoichi Iriguchi & Shin Kaneko

2. Takeda-CiRA Joint Program (T-CiRA), Fujisawa, Kanagawa, Japan

   Sara Shiina, Shoichi Iriguchi & Shin Kaneko

3. Division of Cancer Immunotherapy, Exploratory Oncology Research & Clinical Trial Center, National Cancer Center, Kashiwa, Japan

   Yasushi Uemura

4. Laboratory of Cancer Immunotherapy and Immunology, Transborder Medical Research Center, University of Tsukuba, Tsukuba, Japan

   Shin Kaneko

Contributions

S.S., T.U., S.I., and S.K. designed the study; S.S., T.U., and S.I. interpreted the data; S.S. and T.U. performed the experiments; Y.U. provided critical materials, protocols and advice for the experiments; S.K. supervised the study; S.S., S.I., and S.K. wrote the manuscript.

Corresponding author

Correspondence to Shin Kaneko.

Competing interests

The authors declare the following competing interests: Shin Kaneko is the founder, shareholder, and director of Shinobi Therapeutics, Inc., and has received research funding from Shinobi Therapeutics, Inc., Takeda Pharmaceutical Co., Ltd., Astellas Co., Ltd., Terumo Co., Ltd., Mitsui-soko Co., Ltd. and KOTAI Biotechnologies, Co., Ltd.

Peer review information

Communications Biology thanks the anonymous reviewers for their contribution to the peer review of this work. Primary handling editors: Dr Ophelia Bu and Dr Christina Rosenthal.

Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/.

Reprints and permissions