Abstract LB035: BTN1A1 and YAP1 crosstalk: A key mechanism in tumor immune evasion and therapeutic targeting

Abstract Butyrophilin 1A1 (BTN1A1) is a novel immune checkpoint protein belonging to the butyrophilinfamily. BTN1A1 is expressed in various human tumors, as well as on immune cells. Our findingsindicate a mutual interaction between BTN1A1 and Yes-associated protein 1 (YAP1) expressionin various human solid tumors. Furthermore, BTN1A1 was found to co-localize with nuclearYAP1 expression in cancer patient samples. Previous reports demonstrated that BTN1A1 playsan immunoregulatory role in T cell activation and proliferation. Here, we further show thatBTN1A1 is also involved in the activation and expression of YAP1.YAP1, a key effector of the Hippo signaling pathway, plays a critical role in regulating cellularproliferation, apoptosis, and tissue homeostasis. Dysregulation of YAP1 activity has beenimplicated in several malignancies, including lung and colon cancers. Functional assays revealedthat YAP1 overexpression enhances tumor cell proliferation, migration, and resistance tochemotherapeutic agents. Conversely, YAP1 knockdown or inhibition leads to reduced tumorgrowth and sensitization of cells to therapy.In our analysis, we observed a significant correlation between high levels of BTN1A1 and highlevels of nuclear YAP1 in several cancer patients. To further understand this interaction, weinvestigated the effects of the BTN1A1-YAP1 pathway on lung and colon cancer cells. A549lung cancer cell lines were labeled and cultured as 3D spheroids with human peripheral bloodmononuclear cells (hPBMC), hSTC810, and docetaxel. The A549 spheroids were examined forred fluorescent protein (RFP) disruption following treatment with hPBMC, hSTC810, anddocetaxel, by assessing spheroid size and formation rate. Similarly, LS1034 colon cancer celllines were labeled and cultured as 3D spheroids with hPBMC, hSTC810, and TAS-102. TheLS1034 spheroids were evaluated for RFP disruption after treatment with hPBMC, hSTC810,and TAS-102, by assessing spheroid size and formation rate. In all experiments, the synergisticeffects of hSTC810 in combination with other therapies were analyzed in the context of YAP1expression in the tumor.This study demonstrates that inhibition of BTN1A1 by hSTC810 in cancer cell lines leads tosignificant downregulation of genes associated with the YAP1 response and upregulation of Tcell activation. By simultaneously downregulating YAP1-driven oncogenic pathways andenhancing immune activation, BTN1A1 inhibition offers a novel dual mechanism for combatinglung and colon cancers. These findings pave the way for future clinical exploration of BTN1A1as a key target in cancer immunotherapy. Citation Format: Seung-Hoon Lee, Chunai Wu, Young-Seung Kim, Bong-Ki Hong, Andrew H. Park, Stephen S. Yoo. BTN1A1 and YAP1 crosstalk: A key mechanism in tumor immune evasion and therapeutic targeting [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_2):Abstract nr LB035.