Abstract 881: Innate immune cell-mediated anti-tumor activity against lung cancer and pleural mesothelioma cells

Abstract Objectives: Immune checkpoint inhibitors have played a pivotal role in cancer treatment, and various combination therapies are being developed. However, their add-on effects remain limited, highlighting the urgent need for novel therapeutic modalities. Among various approaches, the adoptive transfer of immune effector cells has attracted particular attention, especially the use of allogeneic immune effector cells due to the frequently immunosuppressed status of cancer patients. We have previously focused on Vδ2 γδ T cells and NK cells, developing methods for their large-scale expansion. These innate immune effector cells are highly suitable for allogeneic adoptive transfer, as they exhibit tumor cytotoxicity independently of the major histocompatibility complex. In this study, we evaluated the cytotoxic properties of these innate immune effector cells, including innate cytotoxicity, antigen-specific cytotoxicity, antibody-dependent cellular cytotoxicity (ADCC), and cytokine production. Materials and Methods: After obtaining informed consent, peripheral blood mononuclear cells (PBMCs) were collected from healthy adults, lung cancer patients, and pleural mesothelioma patients to prepare PBMCs. The PBMCs were stimulated with tetrakis-pivaloyloxymethyl 2-(thiazole-2-ylamino) ethylidene-1, 1-bisphosphonate (PTA), a bisphosphonate prodrug, along with IL-2 to enable the expansion of Vδ2 γδ T cells. The expanded Vδ2 γδ T cells were then co-cultured with human lung cancer cell lines to evaluate their effector functions in vitro. Additionally, CD3-negative PBMCs were cultured with IL-2 and IL-18 to expand NK cells, which were subsequently co-cultured with human pleural mesothelioma cells to assess the effector functions of NK cells in vitro. PTA was used as the antigen, and anti-EGFR antibody was used for ADCC assays. Results: Vδ2 γδ T cells exhibited PTA-dependent cytotoxicity against lung cancer cells. Moreover, Vδ2 γδ T cells with high CD16 expression demonstrated ADCC and IFN-γ production against lung cancer cells. NK cells displayed innate cytotoxicity against pleural mesothelioma cells, and this cytotoxic activity increased in an antibody-dependent manner. Conclusion: The use of PTA/IL-2 enabled the high-purity expansion of Vδ2 γδ T cells, which exhibited robust immune effector functions against lung cancer cells via T cell receptor and CD16-dependent mechanisms. Similarly, IL-2/IL-18 facilitated the high-purity expansion of NK cells, which demonstrated strong innate cytotoxicity and ADCC against pleural mesothelioma cells. Moving forward, in vivo studies are planned to advance the potential for infusion therapy with Vδ2 γδ T cells and NK cells. Citation Format: Hiromi Tomono, Kazumasa Akagi, Yasuhiro Umeyama, Midori Matsuo, Hirokazu Taniguchi, Hiroshi Gyotoku, Shinnosuke Takemoto, Yoshimasa Tanaka, Hiroshi Mukae. Innate immune cell-mediated anti-tumor activity against lung cancer and pleural mesothelioma cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 881.