HER2 CAR-expressing iPSC-derived iNKT cells exhibit multifaceted immunomodulatory functions beyond direct tumor killing
4 affiliations
- 1BrightPath Biotherapeutics Co Ltd, Tokyo, Japan
- 2Laboratory for Developmental Genetics, RIKEN Center for Integrative Medical Sciences, Yokohama, Japan
- 3Department of Medical Immunology, Graduate School of Medicine, Chiba University, Chiba, Japan
- 4Department of Cellular and Molecular Medicine, Graduate School of Medicine, Chiba University, Chiba, Japan
Abstract
Background: Autologous chimeric antigen receptor (CAR)-T cell therapy exhibits remarkable clinical efficacy for hematologic malignancies; however, its efficacy against solid tumors is limited by the immunosuppressive tumor microenvironment and the lack of effective strategies to induce broader antitumor immunity. Invariant natural killer T (iNKT) cells are known to elicit antitumor effects by activating tumor antigen-specific cytotoxic T lymphocytes, promoting dendritic cells maturation, and modulating macrophage activity, thereby providing a mechanism distinct from conventional T cell-based therapies. To couple this immunomodulatory capacity of iNKT cells with CAR technology, we developed allogeneic induced pluripotent stem cell (iPSC)-derived iNKT cells bearing a human epidermal growth factor receptor 2 (HER2) reactive CAR (HER2 CAR) and evaluated their cytotoxic and immunomodulatory functions.
Method: HER2 CAR-expressing iPSC-derived iNKT (HER2 CAR-ipsNKT) cells were generated and characterized for cytotoxic and immunomodulatory functions, including T-cell recruitment, and M2 macrophage re-polarization, and were evaluated for antitumor efficacy in xenograft mouse models.
Results: HER2 CAR-ipsNKT cells specifically recognized HER2-positive tumor cells and exerted potent antitumor activity through NK-like cytotoxicity. In addition to direct tumor killing, HER2 CAR-ipsNKT cells promoted the expansion of tumor-reactive T cells, and this effect was diminished following depletion of CD11c+ cells. HER2 CAR-ipsNKT cells also demonstrated immunomodulatory properties, including T-cell recruitment activity and M2 macrophage killing and re-polarization, supporting remodeling of the tumor immune microenvironment.
Conclusion: Our findings demonstrate that HER2 CAR-ipsNKT cells not only exert direct antitumor activity but also promote CD11c-dependent expansion of antigen-reactive CD8+ T cells, suggesting their capacity to induce broader antitumor immunity.
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BibTeX
@article{shioya2026her2,
title = {{HER2 CAR-expressing iPSC-derived iNKT cells exhibit multifaceted immunomodulatory functions beyond direct tumor killing}},
author = {Koichiro Shioya and Tomio Matsumura and Akane Urakami and Tomokuni Shigeura and Yu-Ching Lin and Mio Fujimaki and Yuji Mishima and Takahiro Aoki and Momoko Okoshi and Kiwamu Motoyoshi and Shinichiro Motohashi and Haruhiko Koseki and Lilin Zhang},
journal = {Journal for Immunotherapy of Cancer},
year = {2026},
month = oct,
doi = {10.1136/jitc-2026-016268},
url = {https://doi.org/10.1136/jitc-2026-016268},
note = {CC BY-NC 4.0},
}
RIS
TY - JOUR
TI - HER2 CAR-expressing iPSC-derived iNKT cells exhibit multifaceted immunomodulatory functions beyond direct tumor killing
AU - Koichiro Shioya
AU - Tomio Matsumura
AU - Akane Urakami
AU - Tomokuni Shigeura
AU - Yu-Ching Lin
AU - Mio Fujimaki
AU - Yuji Mishima
AU - Takahiro Aoki
AU - Momoko Okoshi
AU - Kiwamu Motoyoshi
AU - Shinichiro Motohashi
AU - Haruhiko Koseki
AU - Lilin Zhang
PY - 2026
DA - 2026/10/20
JO - Journal for Immunotherapy of Cancer
DO - 10.1136/jitc-2026-016268
UR - https://doi.org/10.1136/jitc-2026-016268
AB - Background: Autologous chimeric antigen receptor (CAR)-T cell therapy exhibits remarkable clinical efficacy for hematologic malignancies; however, its efficacy against solid tumors is limited by the immunosuppressive tumor microenvironment and the lack of effective strategies to induce broader antitumor immunity. Invariant natural killer T (iNKT) cells are known to elicit antitumor effects by activating tumor antigen-specific cytotoxic T lymphocytes, promoting dendritic cells maturation, and modulating macrophage activity, thereby providing a mechanism distinct from conventional T cell-based therapies. To couple this immunomodulatory capacity of iNKT cells with CAR technology, we developed allogeneic induced pluripotent stem cell (iPSC)-derived iNKT cells bearing a human epidermal growth factor receptor 2 (HER2) reactive CAR (HER2 CAR) and evaluated their cytotoxic and immunomodulatory functions. Method: HER2 CAR-expressing iPSC-derived iNKT (HER2 CAR-ipsNKT) cells were generated and characterized for cytotoxic and immunomodulatory functions, including T-cell recruitment, and M2 macrophage re-polarization, and were evaluated for antitumor efficacy in xenograft mouse models. Results: HER2 CAR-ipsNKT cells specifically recognized HER2-positive tumor cells and exerted potent antitumor activity through NK-like cytotoxicity. In addition to direct tumor killing, HER2 CAR-ipsNKT cells promoted the expansion of tumor-reactive T cells, and this effect was diminished following depletion of CD11c+ cells. HER2 CAR-ipsNKT cells also demonstrated immunomodulatory properties, including T-cell recruitment activity and M2 macrophage killing and re-polarization, supporting remodeling of the tumor immune microenvironment. Conclusion: Our findings demonstrate that HER2 CAR-ipsNKT cells not only exert direct antitumor activity but also promote CD11c-dependent expansion of antigen-reactive CD8+ T cells, suggesting their capacity to induce broader antitumor immunity.
SN - 2051-1426
ER -