Background: Although it has been known that N-glycan moiety in immunoglobulin G (IgG) fragment crystallizable (Fc) region, which affects antigen dependent cellular cytotoxicity (ADCC) activity is different between healthy individuals and cancer patients, the impact of N-glycan structure on cancer treatment is unknown. Here, we evaluated the putative ADCC activity by the N-glycan moiety of IgG-Fc using serum samples and analyzed its association with clinical benefits from immune checkpoint inhibitors (ICIs) in patients with advanced non-small cell lung cancer (NSCLC).
Patients and Methods: Serum samples from healthy volunteers (HVs) were obtained from Tohoku Medical Megabank and chronic obstructive pulmonary disease (COPD) patients were enrolled as a smoking-related non-cancer disease cohort. Serum samples from advanced NSCLC patients receiving ICIs until disease progression or unacceptable toxicity were collected prior treatment. Three IgG fractions (area 1, 2 and 3) corresponding to three peaks identified by affinity chromatography using TSKgel FcR-IIIA-NPR column (Tosoh, Japan) were quantified and the putative ADCC activity was estimated based on the ratio of area 3, which associates with highest ADCC activity, to the whole area (area 3 (%)). Mann-Whitney U-test, Kaplan-Meier methods and the log-rank test were conducted for statistical analyses using JMP Pro software (ver. 14.0).
Results: Forty-two COPD and ninty-six NSCLC patients were registered in the study between Jan 2016 and May 2021 at Wakayama Medical University. Characteristics of the patients were as follows: median age, 70 (range, 49-91); male. 78%; smoker, 79%; previous treatment ≥1, 77%; performance status 0-1, 82%; stage IV, 69%; squamous/non-squamous/unknown, 29/69/2%; nivolumab/pembrolizumab/atezolizumab, 46/42/12%. The objective response rate was 25.0% (24/96). The median progression free survival (PFS) and median overall survival (OS) was 72 days (95%CI, 49 to 127) and 310 days (95% CI, 216 to 453), respectively. The area 3 (%) was significantly lower in NSCLC patients than both HVs and COPD patients (P=0.0002 and p<0.0001, respectively) and no significant difference was observed between HVs and COPD samples. When time-to-event analysis was conducted by dividing into two groups in NSCLC patients at the median of the area 3 (%), OS was significantly longer in patient with higher ratio than those with lower one in both entire cohort (median OS, 952 vs 482; 95% CI, 453 days-not reached (NR) and 233-744 days; p=0.0236) and 2nd line subset (median OS, 952 vs 292; 95% CI, 453 days-NR and 120-692 days; p=0.001). Evaluation of IgG fraction was not associated with tumor response or PFS in this study cohort.
Conclusion: Our results suggest that evaluation of the N-glycan moiety of IgG-Fc in peripheral blood has a potential as a prognostic biomarker in advanced NSCLC patients treated with ICIs.
Citation Format: Jun Oyanagi, Yasuhiro Koh, Yasuyuki Akiyama, Atsushi Morimoto, Koichi Sato, Shunsuke Teraoka, Daichi Fujimoto, Nahomi Tokudome, Atsushi Hayata, Yuichi Ozawa, Hiroaki Akamatsu, Masanori Nakanishi, Hiroki Ueda, Nobuyuki Yamamoto. N-glycan moiety of IgG-Fc region is a prognostic biomarker for advancednon-small cell lung cancertreated with immune checkpoint inhibitors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 516.