Abstract 5234: TGFbeta-conditioned K-NK cells are able to counter immune suppression in the tumor micro-environment

Abstract Recent advances have enabled the use of autologous K-NK cells to treat patients suffering from hematological malignancies. When aiming to treat patients suffering from solid tumors however, the suppressive effects of the tumor microenvironment (TME) and the involvement of other immune cells need to be considered to make a cell therapeutic potentially more effective. TGFβ-conditioning (TGFβ-c), the co-culture of K-NK cells with low-dose TGFβ while undergoing cytokine-mediated expansion, imbues these cells with unique qualities suitable to mitigate immuno-suppressive effects of the TME, making them more efficacious toward solid tumors. The exposure to TGFβ during expansion results in significant downregulation of SMAD3, rendering these cells insensitive to TGFβ-mediated down-regulation of NK cell receptors. TGFβ-c K-NK cells display enhanced in vitro cytotoxicity towards 2D, 3D cultured cell lines as well as against organoid models derived of various indications. These cells infiltrate into patient-derived tumor organoids at higher frequency and have increased IFNγ secretion upon target-specific activation. The effect of the higher IFNγ output on a complementary anti-tumor immune subset was investigated in complex immune cell cultures and was indeed shown to enhance DC maturation. In vivo studies revealed prolonged persistence of TGFβ-c K-NK cells in mice while retaining both altered gene-expression and functional hallmarks for up to 28 days, indicating that the conditioning results in a stable phenotype. In summary, TGFβ-c K-NKs are a platform with enhanced potency to transition cell therapy from treating hematological to solid tumor malignancies. Citation Format: Andre Kunert, Anna Oja, Ieva Cesonyte, Katarzyna Franciszkiewicz, Sukhvinder Sidhu, Hardik Jetani, Giulio Bocconcelli, Robert Igarashi, Valeria R. Fantin. TGFbeta-conditioned K-NK cells are able to counter immune suppression in the tumor micro-environment abstract. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts) ; 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84 (6Suppl): Abstract nr 5234.