Abstract 2908: TIGIT knockout enhances anti-tumor response of Natural Killer cells and prevents fratricide when combined with therapeutic ADCC-competent TIGIT antibodies (2023)

Abstract In this study we propose knockout of the inhibitory receptor TIGIT on Natural Killer (NK) cells enhances their anti-tumor response and prevents NK cell fratricide when combined with ADCC-competent antibodies targeting TIGIT. T cell immunoreceptor with immunoglobulin and ITIM domain (TIGIT) is a major inhibitory receptor of both T cells and NK cells and is an emerging target for immune checkpoint blockade for the treatment of cancer. Although preclinical studies using combinations of anti-TIGIT and anti-PD-(L)1 showed promising results, the phase III SKYSCRAPER-01 trial using the combination of tiragolumab and atezolizumab for NSCLC did not meet its co-primary endpoint of progression free survival (PFS) while the overall survival (OS) at the time of this publication was immature with the study still ongoing. There is critical need to further understand the mechanism of function of TIGIT on immune cells to support its clinical use. Most of the current understanding of TIGIT regulation of immune cell function has been based on T cells, despite comparable or higher TIGIT expression on NK cells. Recent murine studies have shown the therapeutic efficacy of PD-1 and TIGIT blockade depended on the presence of NK cells, indicating they are an important immune population to consider in the efficacy of TIGIT blockade treatments. Furthermore, the majority of TIGIT antibodies have a humanized IgG, which binds to Fc receptors (CD16) and induces antibody-dependent cellular cytotoxicity (ADCC), a major contributor to their efficacy. Since both CD16 and TIGIT are highly expressed on activated NK cells, there is a potential for ADCC-driven fratricide of TIGIT+ NK cells with ADCC-competent anti-TIGIT. In this study, TIGIT knockout was performed in ex vivo-expanded primary human NK cells and anti-tumor response measured. Compared to WT NK cells, TIGIT knockout NK cells had improved in vitro killing of 3D lung cancer spheroids and increased ADCC when combined with cetuximab. TIGIT KO NK cells had upregulated mTORC1 signaling, increased basal glycolytic rate, and increased degranulation. Moreover, fratricide of WT NK cells was observed in the presence of ADCC-competent anti-TIGIT and could be ameliorated by TIGIT knockout. Altogether, this study demonstrated that the highly cytotoxic fratricide resistant TIGIT knockout NK cells have translation potential alone or in combination with ADCC-competent anti-TIGIT antibodies to enhance the efficacy of anti-TIGIT therapeutics. Citation Format: Md Faqrul Hasan, Tayler J. Croom-Perez, Jeremiah L. Oyer, Liza D. Robles-Carrillo, Thomas A. Dieffenthaller, Alicja J. Copik. TIGIT knockout enhances anti-tumor response of Natural Killer cells and prevents fratricide when combined with therapeutic ADCC-competent TIGIT antibodies [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 2908.