Serum levels of soluble CD163 and CXCL5 may be predictive markers for immune-related adverse events in patients with advanced melanoma treated with nivolumab: a pilot study.

Taku Fujimura,Sadanori Furudate,Takeru Funakoshi,Atsushi Otsuka,Kayo Tanita,Takanori Hidaka,Hiroshi Uchi,Setsuya Aiba,Hiroo Hata,Ryota Tanaka,Yota Sato,Yumi Nonomura,Yuki Yamamoto,Yasuhiro Fujisawa,Koji Yoshino,Megumi Aoki,Hisako Okuhira,Kimiaki Imafuku ,Yahiko Kambayashi ,Satoru Matsushita

doi:10.18632/oncotarget.24509

Abstract

Antibodies against PD-1, such as nivolumab and pembrolizumab, are widely used in the treatment of various cancers including advanced melanoma. The anti-PD-1 Ab significantly prolongs survival in patients with metastatic melanoma, and its administration in combination with local or systemic therapy may also lead to improved outcomes. Although anti-PD-1 Ab-based combined therapy might be effective for the treatment of advanced melanoma, the associated risk of irAEs is an important consideration. Therefore, being able to predict irAEs is of great interest to oncologists. The purpose of this study was to evaluate the value of using serum levels of sCD163 and CXCL5 to predict irAEs in patients with advanced melanoma who were administered nivolumab. To this end, we analyzed these serum levels in 46 cases of advanced melanoma treated with nivolumab. In addition, the tumor stroma was evaluated by immunohistochemistry and immunofluorescence. We measured the serum levels of sCD163 and CXCL5 on day 0 (immediately before nivolumab administration) and day 42. The serum absolute levels of sCD163 were significantly increased in patients who developed AEs (p = 0.0018). Although there was no significant difference in serum levels of CXCL5, the absolute value of CXCL5 could at least be a supportive marker for the increased absolute levels of serum sCD163. This study suggests that sCD163 and CXCL5 may serve as possible prognostic biomarkers for irAEs in patients with advanced melanoma treated with nivolumab.

Highlights

The program cell death-1/programmed death-ligand 1 (PD-1/PD-L1) pathway plays a critical role in the tumor immune response; anti-PD-1 antibodies (Abs), such as nivolumab and pembrolizumab, are widely used in the treatment of various cancers including advanced melanoma [1,2,3]
This study suggests that soluble CD163 (sCD163) and CXCL5 may serve as possible prognostic biomarkers for immunerelated adverse events (irAEs) in patients with advanced melanoma treated with nivolumab
CXCL5 is a biomarker of T helper 17 cellmediated autoimmune diseases such as multiple sclerosis, rheumatoid arthritis, and pemphigus vulgaris [16,17,18]; and soluble CD163 is a Tumor-associated macrophages (TAMs) marker that appears in the serum as a result of proteolytic shedding [19]

Summary

Introduction

The program cell death-1/programmed death-ligand 1 (PD-1/PD-L1) pathway plays a critical role in the tumor immune response; anti-PD-1 antibodies (Abs), such as nivolumab and pembrolizumab, are widely used in the treatment of various cancers including advanced melanoma [1,2,3]. Concerning metastatic melanoma, periostin (POSTN) was found to be expressed in the region surrounding melanoma cell nests in the metastatic melanoma lesions of wounded mice and humans [15], suggesting that it might stimulate TAMs to produce chemokines that induce melanoma-specific tumor-infiltrating lymphocytes (TILs) in melanoma patients with systemic inflammation. Upon POSTN stimulation, M2 macrophages produce several immunosuppressive and autoimmune-related chemokines including CXCL5 [14]. We previously reported that both CXCL5 and sCD163 might predict irAEs in 17 patients with advanced melanoma patients treated with nivolumab [8, 20]. We further analyzed the serum levels of sCD163 and CXCL5 in 46 cases of advanced melanoma treated with nivolumab

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