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Significance of soluble PD-L1 for malignant tumors

Asanuma K

Department of Orthopedic Surgery, Mie University School of Medicine, Tsu City, Mie, Japan

E-mail : aa

Nakamura T

Department of Orthopedic Surgery, Mie University School of Medicine, Tsu City, Mie, Japan

Hagi T

Department of Orthopedic Surgery, Mie University School of Medicine, Tsu City, Mie, Japan

Kita K

Department of Orthopedic Surgery, Mie University School of Medicine, Tsu City, Mie, Japan

DOI: 10.15761/JTS.1000286

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Key words

 PD-L1, soluble, soft tissue tumor, soft tissue sarcoma, metastasis, prognosis

The tumor immune microenvironment has drawn attention as a therapeutic target. One immune suppressive protein, PD-L1 (B7-H1 or CD274), a 40-kDa transmembrane glycoprotein, is known as a primary ligand of PD-1. PD-L1 expression has been observed in active T cells, B cells, NK cells, DCs, monocytes, macrophages, activated vascular endothelial cells, mesenchymal stem cells, and tumor cells [1]. The interaction of PD-L1 and PD-1 can induce T cell tolerance [2], T cell apoptosis [3], and T cell exhaustion [4]. The enhancement of this immune suppressive protein leads to evasion of the host immune response and tumor aggravation. A relationship between high PD-L1 expression in tumor tissues and poor prognosis in various malignant tumors such as non-small cell lung cancer [5], ovarian cancer [6], renal cell carcinoma [7], melanoma [8], breast cancer [9], and soft tissue sarcoma [10] has been reported. Thus, it is recognized that PD-L1 expression affects tumor behavior and prognosis.

The circulating soluble form of PD-L1 (sPD-L1) in blood has attracted much attention. In addition to poor prognosis related to high PD-L1 expression in tumors, high sPD-L1 is related to poor prognosis in various cancers such as renal cell carcinoma [11], hepatocellular carcinoma [12], lung cancer [13], gastric cancer [14], and B cell lymphoma [15]. The link between elevated sPD-L1 and poor prognosis indicates that sPD-L1 probably has functional activity. However, its roles have not been fully elucidated. Here, we review the sources and functions of sPD-L1. 

Speculated sources of sPD-L1:

  1. Cleavage and release from membrane PD-L1
  2. Spliced variants
  3. Release by cytokines, cell stress, cell injury, or cell death

Chen, et al. reported that sPD-L1 is released into the culture supernatant and could be decreased by a metalloproteinase (MMP) inhibitor [16]. This means that MMP can release the extracellular domain of membrane PD-L1, leading to sPD-L1. The cleavage site of PD-L1 and the function of cleaved PD-L1 by MMP are still unknown and need further study. Zhou, et al. found four splice variants, PD-L1-1, PD-L1-3, PD-L1-9, and PD-L1-12. It is easy to consider that the variants that lack the transmembrane domain (PD-L1-3, PD-L1-9) are released in the culture medium. However, the variant with a transmembrane domain is also secreted and detected in the culture medium (PD-L1-1). These variants are also observed in the plasma of melanoma patients [17]. In addition, cytokines such as interferon gamma, interferon alpha, and TNF-alpha increase the release of these variants into culture medium [17]. At this time, the possible induction of PD-L1 release by cell stress, cell injury, or cell death cannot be excluded.

Functional assessment of sPD-L1

Functional assessment of sPD-L1 is extremely important. Chen [16].  and Takeuchi [18].  Developed a unique ELISA to detect sPD-L1. They used a PD-1-Ig fusion protein to capture sPD-L1, which possesses binding capacity to PD-1, instead of a capture antibody. This ELISA detected 29 out of 75 plasma samples from patients with non-small cell lung cancer, and detected sPD-L1 with much higher sensitivity and frequency than conventional ELISA. This sPD-L1 can probably transduce signals into cells by binding membrane PD-1. PD-L1 glycosylation is also important. As deglycosylation of PD-L1 reduces the absorbance of the ELISA, deglycosylated PD-L1 probably cannot bind PD-1. Glycosylation is therefore a critical factor for their interaction [18]. Additionally, spliced variants have also had their functions assessed. The variants reduce the number of activated CD4+ and CD8+ T cells [17]., and one variant induces apoptosis of CD4+ T cells more than CD8+ [11]. The variants possess inhibitory functions against T-cell activation and proliferation [17].

We believe that high PD-L1 in tissues and sPD-L1 are involved in poor prognosis. However, regardless of PD-L1 expression, clinical data indicate that patients receive benefits from checkpoint inhibitor therapy [19-24]. For that reason, we need to develop predictive biomarkers to establish which patients are most likely to benefit from checkpoint blockade. From what we know, released sPD-L1 (at least except for deglycosylated PD-L1) can affect T cell biological activity, and this means that circulating sPD-L1 has the potential to induce systemic immune suppression. sPD-L1 may be a biomarker for determining the use of checkpoint inhibitors. However, there are many things about sPD-L1 left to be clarified, and these need further study.



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Editorial Information


Terry Lichtor
Tsuyoshi Hirata
Shinya Mizuno
Giacomo Corrado

Article Type

Mini Review

Publication history

Received date: October 13, 2018
Accepted date: October 29, 2018
Published date: October 31, 2018


©2018 Asanuma K. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.


Asanuma K, Nakamura T, Hagi T, Kita K, Sudo A (2018) Significance of soluble PD-L1 for malignant tumors. J Transl Sci 5: DOI: 10.15761/JTS.1000286

Corresponding author

Kunihiro Asanuma

Mie University, Orthopedic Surgery, 2-174, Edobashi, Tsu City, Mie 514-8507, Japan.

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