Combination of plasma MMPs and PD-1-binding soluble PD-L1 predicts recurrence in gastric cancer and the efficacy of immune checkpoint inhibitors in non-small cell lung cancer

Fumihiko Ando; Takeru Kashiwada; Shoko Kuroda; Takenori Fujii; Ryotaro Takano; Yoshishige Miyabe; Shinobu Kunugi; Takashi Sakatani; Akihiko Miyanaga; Tomoko Asatsuma-Okumura; Masaaki Hashiguchi; Yoshikazu Kanazawa; Ryuji Ohashi; Hiroshi Yoshida; Masahiro Seike; Akihiko Gemma; Yoshiko Iwai

doi:10.3389/fphar.2024.1384731

Combination of plasma MMPs and PD-1-binding soluble PD-L1 predicts recurrence in gastric cancer and the efficacy of immune checkpoint inhibitors in non-small cell lung cancer

Front Pharmacol. 2024 May 7:15:1384731. doi: 10.3389/fphar.2024.1384731. eCollection 2024.

Authors

Fumihiko Ando^#^{1

2}, Takeru Kashiwada^#³, Shoko Kuroda¹, Takenori Fujii⁴, Ryotaro Takano^{1

2}, Yoshishige Miyabe^{1

5}, Shinobu Kunugi⁶, Takashi Sakatani⁴, Akihiko Miyanaga³, Tomoko Asatsuma-Okumura¹, Masaaki Hashiguchi¹, Yoshikazu Kanazawa², Ryuji Ohashi⁴, Hiroshi Yoshida², Masahiro Seike³, Akihiko Gemma³, Yoshiko Iwai¹

Affiliations

¹ Department of Cell Biology, Institute for Advanced Medical Sciences, Nippon Medical School, Tokyo, Japan.
² Department of Gastrointestinal and Hepato-Biliary-Pancreatic Surgery, Nippon Medical School, Tokyo, Japan.
³ Department of Pulmonary Medicine and Oncology, Nippon Medical School, Tokyo, Japan.
⁴ Department of Integrated Diagnostic Pathology, Nippon Medical School, Tokyo, Japan.
⁵ Department of Immunology and Parasitology, St. Marianna University School of Medicine, Kawasaki, Kanagawa, Japan.
⁶ Department of Analytic Human Pathology, Nippon Medical School, Tokyo, Japan.

^# Contributed equally.

Abstract

Background: The tumor microenvironment (TME) impacts the therapeutic efficacy of immune checkpoint inhibitors (ICIs). No liquid biomarkers are available to evaluate TME heterogeneity. Here, we investigated the clinical significance of PD-1-binding soluble PD-L1 (bsPD-L1) in gastric cancer (GC) patients and non-small cell lung cancer (NSCLC) patients treated with PD-1/PD-L1 blockade.

Methods: We examined bsPD-L1, matrix metalloproteinases (MMPs), and IFN-γ levels in plasma samples from GC patients (n = 117) prior to surgery and NSCLC patients (n = 72) prior to and 2 months after ICI treatment. We also examined extracellular matrix (ECM) integrity, PD-L1 expression, and T cell infiltration in tumor tissues from 25 GC patients by Elastica Masson-Goldner staining and immunohistochemical staining for PD-L1 and CD3, respectively.

Results: bsPD-L1 was detected in 17/117 GC patients and 16/72 NSCLC patients. bsPD-L1 showed strong or moderate correlations with plasma MMP13 or MMP3 levels, respectively, in both GC and NSCLC patients. bsPD-L1 expression in GC was associated with IFN-γ levels and intra-tumoral T cell infiltration, whereas MMP13 levels were associated with loss of ECM integrity, allowing tumor cells to access blood vessels. Plasma MMP3 and MMP13 levels were altered during ICI treatment. Combined bsPD-L1 and MMP status had higher predictive accuracy to identify two patient groups with favorable and poor prognosis than tumor PD-L1 expression: bsPD-L1⁺MMP13^high in GC and bsPD-L1⁺(MMP3 and MMP13)^increased in NSCLC were associated with poor prognosis, whereas bsPD-L1⁺MMP13^low in GC and bsPD-L1⁺(MMP3 or MMP13)^decreased in NSCLC were associated with favorable prognosis.

Conclusion: Plasma bsPD-L1 and MMP13 levels indicate T cell response and loss of ECM integrity, respectively, in the TME. The combination of bsPD-L1 and MMPs may represent a non-invasive tool to predict recurrence in GC and the efficacy of ICIs in NSCLC.

Keywords: MMP13; T cell response; extracellular matrix integrity; soluble PD-L1; tumor microenvironment.

Grants and funding

The author(s) declare that financial support was received for the research, authorship, and/or publication of this article. This work was supported by the Grant-in-Aid for Scientific Research from the Japan Society for the Promotion of Science (JP19K07783 and JP22K07262 to YI) and a research grant from Sysmex Corporation (to YI).