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.
GrantsErnst-Jung-Stiftung Melanoma Research Alliance Grants Marie-Sklodowska-Curie Program Training Network for the Immunotherapy of Cancer - H2020 Program of the European Union Marie-Sklodowska-Curie Program Training Network for Optimizing Adoptive T Cell Therapy of Cancer - H2020 Program of the European Union Hector foundation Else Kroner-Fresenius-Stiftung LMU Munich's Institutional Strategy LMUexcellent Bundesministerium fur Bildung und Forschung Project Oncoattract European Research Council German Research Foundation (DFG) NIH Fritz-Bender Foundation European Research Council (ERC) under the European Union's Horizon 2020 research and innovation program Volkswagen Foundation (project OntoTime) Jose-Carreras Foundation Deutsche Gesellschaft fur Immun-und Targeted-therapie German Cancer Aid International Doctoral Program i-Target: Immunotargeting of Cancer - Elite Network of Bavaria