Abstract 2046: Coefficient variation of glycosylphosphatidylinositol-anchored 80 kDa protein (GPI-80) on neutrophil status in metastatic renal cell carcinoma (MRCC) patients treated with combination therapy of nivolumab plus ipilimumab

Abstract Introduction: Immature neutrophils suppress T cell immunity as myeloid-derived suppressor cells. However, recent studies have demonstrated that neutrophils are essential for eradicating antigenically heterogenous tumors via T cell immunotherapies, and CTLA-4 antibodies can recruit neutrophils into tumors. Our previous research identified GPI-80 as a marker of neutrophil maturation, where the coefficient variation of GPI-80 (GPI-80 CV) inversely correlated with the T cell proliferation. We also demonstrated that MRCC patients with high GPI-80 CV had a poor prognosis before the advent of immune-checkpoint inhibitors (ICI). The aim of this study is to investigate the association between GPI-80 CV and the inflammatory marker C-reactive protein (CRP) status and prognosis in mRCC patients treated with the combination therapy of anti-PD-1 nivolumab plus anti-CTLA-4 ipilimumab (NI). Methods: Prior to ICI treatment, peripheral blood samples were collected from 25 patients treated with NI and 10 patients treated with nivolumab monotherapy. GPI-80 was measured using flow cytometry. NI response was categorized as follows: EPD (early progressive disease; disease progressed within 60 days), LPD (late progressive disease; disease progressed between 60 days and 2 years), DR (durable response; disease did not progress beyond 2 years). Results: In NI, GPI-80 CV was significantly higher in durable responder DR patients (P = 0.03, Steel-Dwass test) and marginally higher in EPD patients (P = 0.08) compared to LPD patients. Serum CRP was significantly higher in EPD compared to DR (P = 0.03). When patients were divided into groups 1-3 according to GPI-80 CV and CRP levels: group 1, >10 mg/dl CRP; group 2, <10 mg/dl CRP and <36 GPI-80 CV; group 3, <10 mg/dl CRP and >36 GPI-80 CV. Group 3 had significantly better time-to-treatment-failure (TTF) and overall survival (OS) compared to Group 1 (HR = 0.36 and 95% CI = 0.17-0.73 in TTF, HR = 0.29 and 95% CI = 0.12-0.67 in OS) and Group 2 (HR = 0.15 and 95% CI = 0.03-0.62 in TTF, HR = 0.18 and 95% CI = 0.03-0.93 in OS). In nivolumab monotherapy, TTF OS did not differ between these groups (HR = 1.85 and 95% CI = 0.41-8.16 in group 3 vs. group 2). Conclusions: In patients receiving NI therapy, high GPI-80 CV—a marker of immature neutrophils—was associated with improved TTF and OS. This association was not observed with nivolumab monotherapy, suggesting a unique role for neutrophil immaturity in the efficacy of combination immunotherapy including CTLA-4 blockade. The combination of GPI-80 and CRP is a candidate for predictive biomarker for NI efficacy in MRCC. Citation Format: Sei Naito, Yuji Takeda, Sabrina Saima, Hiromi Ito, Tomoyuki Kato, Takafumi Narisawa, Yuki Takai, Shinta Suenaga, Mayu Yagi, Hisanobu Asao, Norihiko Tsuchiya. Coefficient variation of glycosylphosphatidylinositol-anchored 80 kDa protein (GPI-80) on neutrophil status in metastatic renal cell carcinoma (MRCC) patients treated with combination therapy of nivolumab plus ipilimumab [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 2046.