Generation of hypoimmunogenic gastric insulin-secreting organoids

Dattoli, A. A.; Brown, M. E.; Feinsten, Z.; Pearson, B.; Lang, Y.; Polavarapu, V.; Zhou, M.; Nachman, R.; Kelemen, Y.; Rafii, S.; Creusot, R. J.; Brusko, T.; Zhou, J.; Huang, X.

doi:10.64898/2026.07.08.736836

bioRxiv · 10.64898/2026.07.08.736836

Generation of hypoimmunogenic gastric insulin-secreting organoids

Dattoli, A. A.·Brown, M. E.·Feinsten, Z.·Pearson, B.·Lang, Y.·Polavarapu, V.·Zhou, M.·Nachman, R.·Kelemen, Y.·Rafii, S.·Creusot, R. J.·Brusko, T.·Zhou, J.·Huang, X.

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Abstract

Gastric insulin-secreting organoids (GINS) represent a promising source of {beta}-like cells for type 1 diabetes (T1D) therapy. In same-donor comparisons with induced pluripotent stem cell-derived islets (iPSC-islets), GINS displayed robust glucose responsiveness and reduced expression of key T1D autoantigens. Importantly, GINS exhibited decreased susceptibility to cytotoxicity mediated by engineered HLA-matched preproinsulin-specific effector T cells (Avatar Teffs) and a distinct transcriptional profile enriched for immune-modulatory and stress-adaptive gene programs. To enhance immune evasion, we engineered gastric stem cells to overexpress Programmed Death Ligand 1 (PD-L1) in an inducible manner. PD-L1+ GINS maintained normal functionality, while exhibiting improved survival under allogeneic Avatar Teff challenge in a MHC class I-independent fashion. We evaluated PD-L1-mediated protection against autologous Avatar Teff attack using an endothelialized microfluidic platform recapitulating physiologic immune interactions. T cells show reduced infiltration into PD-L1 GINS, resulting in significantly higher organoid viability compared to control GINS. Together, these findings identify GINS as a functional and engineerable {beta}-like cell platform with intrinsic hypoimmunogenic features, and support PD-L1 engineering as a strategy to enhance immune protection for both allogeneic and autologous transplantation in T1D.

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Dattoli, A. A., Brown, M. E., Feinsten, Z., Pearson, B., Lang, Y., Polavarapu, V., Zhou, M., Nachman, R., Kelemen, Y., Rafii, S., Creusot, R. J., Brusko, T., Zhou, J., Huang, X.. 2026-07-13. Generation of hypoimmunogenic gastric insulin-secreting organoids. https://doi.org/10.64898/2026.07.08.736836

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