Combined targeting of soluble latent TGF-beta and a solid tumor-associated antigen with adapter CAR T cells

Werchau, Niels; Kotter, Bettina; Criado-Moronati, Elvira; Gosselink, Andre; Cordes, Nicole; Lock, Dominik; Lennartz, Simon; Kolbe, Carolin; Winter, Nora; Teppert, Karin; Engert, Fabian; Webster, Brian; Mittelstaet, Jörg; Schaefer, Daniel; Mallmann, Peter; Mallmann, Michael R.; Ratiu, Dominik; Assenmacher, Mario; Schaser, Thomas; Bergwelt-Baildon, Michael von; Abramowski, Pierre und Kaiser, Andrew D. (2022): Combined targeting of soluble latent TGF-beta and a solid tumor-associated antigen with adapter CAR T cells. In: Oncoimmunology, Bd. 11, Nr. 1, e2140534

Abstract

Solid tumors consist of malignant and nonmalignant cells that together create the local tumor microenvironment (TME). Additionally, the TME is characterized by the expression of numerous soluble factors such as TGF-beta. TGF-beta plays an important role in the TME by suppressing T cell effector function and promoting tumor invasiveness. Up to now CAR T cells exclusively target tumor-associated antigens (TAA) located on the cell membrane. Thus, strategies to exploit soluble antigens as CAR targets within the TME are needed. This study demonstrates a novel approach using Adapter CAR (AdCAR) T cells for the detection of soluble latent TGF-beta within the TME of a pancreatic tumor model. We show that AdCARs in combination with the respective adapter can be used to sense soluble tumor-derived latent TGF-beta, both in vitro and in vivo. Sensing of the soluble antigen induced cellular activation and effector cytokine production in AdCAR T cells. Moreover, we evaluated AdCAR T cells for the combined targeting of soluble latent TGF-beta and tumor cell killing by targeting CD66c as TAA in vivo. In sum, our study broadens the spectrum of targetable moieties for AdCAR T cells by soluble latent TGF-beta.

• Dokumententyp: Zeitschriftenartikel
• Fakultät: Medizin
• Themengebiete: 600 Technik, Medizin, angewandte Wissenschaften > 610 Medizin und Gesundheit
• ISSN: 2162-402X
• Sprache: Englisch