Preprint Article Version 1 Preserved in Portico This version is not peer-reviewed

Significance of Lipopolysaccharides in Gastric Cancer and their Potential as a Biomarker for Nivolumab Sensitivity

Nobuhiro Nakazawa
ORCID logo ,
Takehiko Yokobori
* ORCID logo ,
Makoto Sohda
* ,
Nobuhiro Hosoi
,
Takayoshi Watanabe
,
Yuki Shimoda
,
Munenori Ide
,
Akihiko Sano
,
Makoto Sakai
,
Bilguun Erkhem-Ochir
,
Hiroomi Ogawa
,
Ken Shirabe
,
Hiroshi Saeki
Version 1 : Received: 20 June 2023 / Approved: 21 June 2023 / Online: 21 June 2023 (07:28:13 CEST)

A peer-reviewed article of this Preprint also exists.

Nakazawa, N.; Yokobori, T.; Sohda, M.; Hosoi, N.; Watanabe, T.; Shimoda, Y.; Ide, M.; Sano, A.; Sakai, M.; Erkhem-Ochir, B.; Ogawa, H.; Shirabe, K.; Saeki, H. Significance of Lipopolysaccharides in Gastric Cancer and Their Potential as a Biomarker for Nivolumab Sensitivity. Int. J. Mol. Sci. 2023, 24, 11790. Nakazawa, N.; Yokobori, T.; Sohda, M.; Hosoi, N.; Watanabe, T.; Shimoda, Y.; Ide, M.; Sano, A.; Sakai, M.; Erkhem-Ochir, B.; Ogawa, H.; Shirabe, K.; Saeki, H. Significance of Lipopolysaccharides in Gastric Cancer and Their Potential as a Biomarker for Nivolumab Sensitivity. Int. J. Mol. Sci. 2023, 24, 11790.

Abstract

Lipopolysaccharides are a type of polysaccharide mainly present in the bacterial outer membrane of Gram-negative bacteria. Recent studies have revealed that lipopolysaccharides contribute to the immune response of the host by functioning as a cancer antigen. We retrospectively recruited 198 patients with gastric cancer who underwent surgery. The presence of lipopolysaccharides was determined using immunohistochemical staining, with the intensity score indicating positivity. The relationship between lipopolysaccharides and CD8, PD-L1, TGFBI (a representative downstream gene of TGF-β signaling), E-cadherin, and claudin-4 (epithelial–mesenchymal transition markers) was also investigated. Thereafter, we identified 20 patients with advanced gastric cancer receiving nivolumab and investigated the relationship between lipopolysaccharides and nivolumab sensitivity. After staining for lipopolysaccharides in the nucleus of cancer cells, 150 negative (75.8%) and 48 positive cases (24.2%) were found. The lipopolysaccharide-positive group showed increased cancer stromal TGFBI expression (p < 0.0001) and PD-L1 expression in cancer cells (p = 0.0029). Lipopolysaccharide positivity was significantly correlated with decreased E-cadherin expression (p = 0.0055) and claudin-4 expression (p = 0.029); however, no significant correlation was found between lipopolysaccharide expression and overall survival rate (p = 0.71). Among cases receiving nivolumab, the lipopolysaccharide-negative and -positive groups had a disease control rate of 66.7% and 11.8%, respectively (p = 0.049). Lipopolysaccharide positivity was associated with TGF-β signaling and epithelial–mesenchymal transition and was considered to promote therapeutic resistance to nivolumab.

Keywords

epithelial–mesenchymal transition (EMT); Gastric cancer; lipopolysaccharides (LPS); Nivolumab; TGF-β

Subject

Medicine and Pharmacology, Gastroenterology and Hepatology

Copyright: This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

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