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bioRxiv · 10.1101/2024.09.04.611205

Identification of small molecule enhancers of NK cell tumoricidal activity via a tumor microenvironment-mimicking co-culture assay

Binici, A.·Hennes, E.·Koska, S.·Niemann, J.·Reich, A.·Pfaff, C.·Sievers, S.·Kahnt, A.·Thomas, D.·Ziegler, S.·Watzl, C.·Waldmann, H.
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Abstract

The tumor microenvironment (TME) is a pro-cancerous niche harboring immunosuppressive factors that are secreted by cancer cells and the surrounding cancer-supportive tissue, such as kynurenine, prostaglandin E2 and transforming growth factor {beta} (TGF{beta}). These factors dampen the activity of cytotoxic lymphocytes like natural killer (NK) cells, allowing evasion of immune cell-mediated killing. To identify small molecules that counteract the immunosuppressive effect of the TME and restore NK cell-mediated cytotoxicity, we developed a phenotypic co-culture assay of cancer cells and primary lymphocytes suitable for medium-throughput screening. We discovered small molecules that restore NK cell-mediated cytotoxicity through diverse mechanisms. The potent TGF{beta} type I receptor (TGF{beta}R-1) inhibitor, RepSox, stood out as superior to other TGF{beta}R-1 inhibitors due to its ability to abolish the effects of both inhibitory factors used in our setup. This mode of action goes beyond TGF{beta}R-1 inhibition and is related to the simultaneous abrogation of cyclooxygenase 1 (COX1) activity.

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Binici, A., Hennes, E., Koska, S., Niemann, J., Reich, A., Pfaff, C., Sievers, S., Kahnt, A., Thomas, D., Ziegler, S., Watzl, C., Waldmann, H.. 2024-09-07. Identification of small molecule enhancers of NK cell tumoricidal activity via a tumor microenvironment-mimicking co-culture assay. https://doi.org/10.1101/2024.09.04.611205

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