Immune mediators as predictive biomarkers for anti-PD-1 antibody therapy in urothelial carcinoma

Yosuke Shibata; Takeshi Kishida; Taku Kouro; Feifei Wei; Yuka Igarashi; Hidetomo Himuro; Takeaki Noguchi; Mitsuyuki Koizumi; Takahisa Suzuki; Kimito Osaka; Yusuke Saigusa; Tetsuro Sasada

doi:10.3389/fphar.2023.1269935

Immune mediators as predictive biomarkers for anti-PD-1 antibody therapy in urothelial carcinoma

Front Pharmacol. 2023 Nov 13:14:1269935. doi: 10.3389/fphar.2023.1269935. eCollection 2023.

Authors

Yosuke Shibata¹, Takeshi Kishida¹, Taku Kouro^{2

3}, Feifei Wei^{2

3}, Yuka Igarashi^{2

3}, Hidetomo Himuro^{2

3}, Takeaki Noguchi¹, Mitsuyuki Koizumi¹, Takahisa Suzuki¹, Kimito Osaka¹, Yusuke Saigusa⁴, Tetsuro Sasada^{2

3}

Affiliations

¹ Department of Urology, Kanagawa Cancer Center, Yokohama, Kanagawa, Japan.
² Division of Cancer Immunotherapy, Kanagawa Cancer Center Research Institute, Yokohama, Kanagawa, Japan.
³ Cancer Vaccine and Immunotherapy Center, Kanagawa Cancer Center, Yokohama, Kanagawa, Japan.
⁴ Department of Biostatistics, School of Medicine, Yokohama City University, Yokohama, Kanagawa, Japan.

Abstract

Introduction: This study aimed to identify immune mediators, including cytokines, chemokines, and growth factors, in the plasma for predicting treatment efficacy and immune-related adverse events (irAEs) in advanced urothelial carcinoma (aUC) treated with immune checkpoint inhibitors (ICIs). Methods: We enrolled 57 patients with aUC who were treated with the anti-programmed cell death protein 1 (PD-1) antibody pembrolizumab after the failure of platinum-based chemotherapy between February 2018 and December 2020. Plasma levels of 73 soluble immune mediators were measured before and 6 weeks after initiating pembrolizumab therapy. The association of estimated soluble immune mediators with clinical outcomes, including overall survival (OS), progression-free survival (PFS), anti-tumor responses, and irAEs, were statistically evaluated. Results: In the multivariate analysis, levels of 18 factors at baseline and 12 factors during treatment were significantly associated with OS. Regarding PFS, baseline levels of 17 factors were significantly associated with PFS. Higher levels of interleukin (IL)-6, IL-8, soluble tumor necrosis factor receptor 1 (sTNF-R1), and IL-12 (p40), both at baseline and post-treatment, were significantly associated with worse OS. Conversely, low IL-6 and high TWEAK levels at baseline were associated with irAEs. Among identified factors, interferon (IFN) γ and IL-12 (p40) were repeatedly identified; high baseline levels of these factors were risk factors for worse OS and PFS, as well as progressive disease. Notably, using correlation and principal component analysis, factors significantly associated with clinical outcomes were broadly classified into three groups exhibiting similar expression patterns. Discussion: Measuring plasma levels of soluble immune mediators, such as IL-6, IL-8, sTNF-R1, IFNγ, and IL-12 (p40), could be recommended for predicting prognosis and irAEs in ICI-treated patients with aUC.

Keywords: anti-PD-1 antibody; chemokine; cytokine; immune checkpoint inhibitors; immune-related adverse event; pembrolizumab.

Grants and funding

The author(s) declare financial support was received for the research, authorship, and/or publication of this article. This study was funded by AMED (Grant Number JP19ae0101076) and Kanagawa Cancer Center Hospital-Research Institute Joint Study (Grant Number 2020-14).