Combined tumor-directed recruitment and protection from immune suppression enable CAR T cell efficacy in solid tumors

Bruno L. Cadilha, Mohamed Reda Benmebarek, Klara Dorman, Arman Oner, Theo Lorenzini, Hannah Obeck, Mira Vänttinen, Mauro Di Pilato, Jasper N. Pruessmann, Stefan Stoiber, Duc Huynh, Florian Märkl, Matthias Seifert, Katrin Manske, Javier Suarez-Gosalvez, Yi Zeng, Stefanie Lesch, Clara H. Karches, Constanze Heise, Adrian GottschlichMoritz Thomas, Carsten Marr, Jin Zhang, Dharmendra Pandey, Tobias Feuchtinger, Marion Subklewe, Thorsten R. Mempel, Stefan Endres, Sebastian Kobold

Research output: Contribution to journalArticlepeer-review

16 Scopus citations

Abstract

CAR T cell therapy remains ineffective in solid tumors, due largely to poor infiltration and T cell suppression at the tumor site. T regulatory (Treg) cells suppress the immune response via inhibitory factors such as transforming growth factor–β (TGF-β). Treg cells expressing the C-C chemokine receptor 8 (CCR8) have been associated with poor prognosis in solid tumors. We postulated that CCR8 could be exploited to redirect effector T cells to the tumor site while a dominant-negative TGF-β receptor 2 (DNR) can simultaneously shield them from TGF-β. We identified that CCL1 from activated T cells potentiates a feedback loop for CCR8+ T cell recruitment to the tumor site. This sustained and improved infiltration of engineered T cells synergized with TGF-β shielding for improved therapeutic efficacy. Our results demonstrate that addition of CCR8 and DNR into CAR T cells can render them effective in solid tumors.

Original languageEnglish (US)
Article numbereabi5781
JournalScience Advances
Volume7
Issue number24
DOIs
StatePublished - Jun 2021
Externally publishedYes

ASJC Scopus subject areas

  • General

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