1. Combined tumor-directed recruitment and protection from immune suppression enable CAR T cell efficacy in solid tumors
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Bruno L. Cadilha, Klara Dorman, Marion Subklewe, C. Karches, Jasper N. Pruessmann, Stefanie Lesch, Moritz Thomas, Stefan Endres, Florian Märkl, Matthias Seifert, Sebastian Kobold, Carsten Marr, Jin Zhang, Duc Huynh, Mauro Di Pilato, Theo Lorenzini, Javier Suarez-Gosalvez, Mira Vänttinen, Dharmendra Pandey, Yi Zeng, Katrin Manske, S Stoiber, M. Benmebarek, Constanze Heise, Thorsten R. Mempel, A Öner, Hannah Obeck, Tobias Feuchtinger, and Adrian Gottschlich
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T cell ,CCL1 ,CCR8 ,T-Lymphocytes, Regulatory ,03 medical and health sciences ,Chemokine receptor ,0302 clinical medicine ,Immune system ,Transforming Growth Factor beta ,Neoplasms ,medicine ,Humans ,Receptor ,Research Articles ,Cancer ,030304 developmental biology ,0303 health sciences ,Multidisciplinary ,Chemistry ,Effector ,SciAdv r-articles ,ddc ,3. Good health ,medicine.anatomical_structure ,030220 oncology & carcinogenesis ,Cancer research ,Research Article ,Transforming growth factor - Abstract
The combination of directed migration and immunosuppressive shielding enables effective T cell therapy in solid tumors., 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.
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