Skip to main content
Top
Published in: World Journal of Surgical Oncology 1/2024

Open Access 01-12-2024 | Gastric Cancer | Research

Involvement of CX3CR1+ cells appearing in the abdominal cavity in the immunosuppressive environment immediately after gastric cancer surgery

Authors: Seiji Natsuki, Mami Yoshii, Hiroaki Tanaka, Takuya Mori, Sota Deguchi, Yuichiro Miki, Tatsuro Tamura, Takahiro Toyokawa, Shigeru Lee, Kiyoshi Maeda

Published in: World Journal of Surgical Oncology | Issue 1/2024

Login to get access

Abstract

Background

Gastric cancer is primarily treated by surgery; however, little is known about the changes in the intraperitoneal immune environment and the prognostic impact of surgery. Surgical stress and cancer-associated inflammation cause immune cells to mobilize into the abdominal cavity via numerous cytokines. One such cytokine, CX3CR1, has various immune-related functions that remain to be fully explained. We characterized the intraperitoneal immune environment by investigating CX3CR1+ cells in intraperitoneal lavage fluid during gastric cancer surgery.

Methods

Lavage fluid samples were obtained from a total of 41 patients who underwent gastrectomy. The relative expression of various genes was analyzed using quantitative real-time PCR. The association of each gene expression with clinicopathological features and surgical outcomes was examined. The fraction of CX3CR1+ cells was analyzed by flow cytometry. Cytokine profiles in lavage fluid samples were investigated using a cytometric beads array.

Results

CX3CR1high patients exhibited higher levels of perioperative inflammation in blood tests and more recurrences than CX3CR1low patients. CX3CR1high patients tended to exhibit higher pathological T and N stage than CX3CR1low patients. CX3CR1 was primarily expressed on myeloid-derived suppressor cells and tumor-associated macrophages. In particular, polymorphonuclear myeloid-derived suppressor cells were associated with perioperative inflammation, pathological N, and recurrences. These immunosuppressive cells were associated with a trend toward unfavorable prognosis. Moreover, CX3CR1 expression was correlated with programmed death–1 expression.

Conclusions

Our results suggest that CX3CR1+ cells are associated with an acute inflammatory response, tumor-promotion, and recurrence. CX3CR1 expression could be taken advantage of as a beneficial therapeutic target for improving immunosuppressive state in the future. In addition, analysis of intra-abdominal CX3CR1+ cells could be useful for characterizing the immune environment after gastric cancer surgery.
Appendix
Available only for authorised users
Literature
1.
go back to reference Yoshii M, Tanaka H, Ohira M, Muguruma K, Lee T, Sakurai K, Kubo N, Maeda K, Hirakawa K. Regulation of neutrophil infiltration into peritoneal cavity by laparoscopic gastrectomy. Hepatogastroenterology. 2015;62:546–50.PubMed Yoshii M, Tanaka H, Ohira M, Muguruma K, Lee T, Sakurai K, Kubo N, Maeda K, Hirakawa K. Regulation of neutrophil infiltration into peritoneal cavity by laparoscopic gastrectomy. Hepatogastroenterology. 2015;62:546–50.PubMed
2.
go back to reference Combadiere C, Salzwedel K, Smith ED, Tiffany HL, Berger EA, Murphy PM. Identification of CX3CR1. A chemotactic receptor for the human CX3C chemokine fractalkine and a fusion coreceptor for HIV-1. J Biol Chem. 1998;273:23799–804.CrossRefPubMed Combadiere C, Salzwedel K, Smith ED, Tiffany HL, Berger EA, Murphy PM. Identification of CX3CR1. A chemotactic receptor for the human CX3C chemokine fractalkine and a fusion coreceptor for HIV-1. J Biol Chem. 1998;273:23799–804.CrossRefPubMed
3.
go back to reference Korbecki J, Simińska D, Kojder K, Grochans S, Gutowska I, Chlubek D, Baranowska-Bosiacka I. Fractalkine/CX3CL1 in Neoplastic Processes. Int J Mol Sci. 2020;21:3723.CrossRefPubMedPubMedCentral Korbecki J, Simińska D, Kojder K, Grochans S, Gutowska I, Chlubek D, Baranowska-Bosiacka I. Fractalkine/CX3CL1 in Neoplastic Processes. Int J Mol Sci. 2020;21:3723.CrossRefPubMedPubMedCentral
4.
go back to reference Imai T, Hieshima K, Haskell C, Baba M, Nagira M, Nishimura M, Kakizaki M, Takagi S, Nomiyama H, Schall TJ, Yoshie O. Identification and Molecular Characterization of Fractalkine Receptor CX<sub>3</sub>CR1, which Mediates Both Leukocyte Migration and Adhesion. Cell. 1997;91:521–30.CrossRefPubMed Imai T, Hieshima K, Haskell C, Baba M, Nagira M, Nishimura M, Kakizaki M, Takagi S, Nomiyama H, Schall TJ, Yoshie O. Identification and Molecular Characterization of Fractalkine Receptor CX<sub>3</sub>CR1, which Mediates Both Leukocyte Migration and Adhesion. Cell. 1997;91:521–30.CrossRefPubMed
5.
go back to reference Schmall A, Al-tamari HM, Herold S, Kampschulte M, Weigert A, Wietelmann A, Vipotnik N, Grimminger F, Seeger W, Pullamsetti SS, Savai R. Macrophage and Cancer Cell Cross-talk via CCR2 and CX3CR1 Is a Fundamental Mechanism Driving Lung Cancer. American Journal of Respiratory and Critical Care Medicine. 2014;191:437–47.CrossRef Schmall A, Al-tamari HM, Herold S, Kampschulte M, Weigert A, Wietelmann A, Vipotnik N, Grimminger F, Seeger W, Pullamsetti SS, Savai R. Macrophage and Cancer Cell Cross-talk via CCR2 and CX3CR1 Is a Fundamental Mechanism Driving Lung Cancer. American Journal of Respiratory and Critical Care Medicine. 2014;191:437–47.CrossRef
6.
go back to reference Ma X, Wang M, Yin T, Zhao Y, Wei X. Myeloid-Derived Suppressor Cells Promote Metastasis in Breast Cancer After the Stress of Operative Removal of the Primary Cancer. Front Oncol. 2019;9:855.CrossRefPubMedPubMedCentral Ma X, Wang M, Yin T, Zhao Y, Wei X. Myeloid-Derived Suppressor Cells Promote Metastasis in Breast Cancer After the Stress of Operative Removal of the Primary Cancer. Front Oncol. 2019;9:855.CrossRefPubMedPubMedCentral
7.
go back to reference Wei LM, Cao S, Yu WD, Liu YL, Wang JT. Overexpression of CX3CR1 is associated with cellular metastasis, proliferation and survival in gastric cancer. Oncol Rep. 2015;33:615–24.CrossRefPubMed Wei LM, Cao S, Yu WD, Liu YL, Wang JT. Overexpression of CX3CR1 is associated with cellular metastasis, proliferation and survival in gastric cancer. Oncol Rep. 2015;33:615–24.CrossRefPubMed
8.
go back to reference Yamauchi T, Hoki T, Oba T, Jain V, Chen H, Attwood K, Battaglia S, George S, Chatta G, Puzanov I, Morrison C, Odunsi K, Segal BH, Dy GK, Ernstoff MS, Ito F. T-cell CX3CR1 expression as a dynamic blood-based biomarker of response to immune checkpoint inhibitors. Nat Commun. 2021;12:1402.ADSCrossRefPubMedPubMedCentral Yamauchi T, Hoki T, Oba T, Jain V, Chen H, Attwood K, Battaglia S, George S, Chatta G, Puzanov I, Morrison C, Odunsi K, Segal BH, Dy GK, Ernstoff MS, Ito F. T-cell CX3CR1 expression as a dynamic blood-based biomarker of response to immune checkpoint inhibitors. Nat Commun. 2021;12:1402.ADSCrossRefPubMedPubMedCentral
9.
go back to reference Yamauchi T, Hoki T, Oba T, Saito H, Attwood K, Sabel MS, Chang AE, Odunsi K, Ito F. CX3CR1-CD8+ T cells are critical in antitumor efficacy but functionally suppressed in the tumor microenvironment. JCI Insight. 2020;5:e133920.CrossRefPubMedPubMedCentral Yamauchi T, Hoki T, Oba T, Saito H, Attwood K, Sabel MS, Chang AE, Odunsi K, Ito F. CX3CR1-CD8+ T cells are critical in antitumor efficacy but functionally suppressed in the tumor microenvironment. JCI Insight. 2020;5:e133920.CrossRefPubMedPubMedCentral
10.
go back to reference Yan Y, Cao S, Liu X, Harrington SM, Bindeman WE, Adjei AA, Jang JS, Jen J, Li Y, Chanana P, Mansfield AS, Park SS, Markovic SN, Dronca RS, Dong H. CX3CR1 identifies PD-1 therapy-responsive CD8+ T cells that withstand chemotherapy during cancer chemoimmunotherapy. JCI Insight. 2018;3:e97828.CrossRefPubMedPubMedCentral Yan Y, Cao S, Liu X, Harrington SM, Bindeman WE, Adjei AA, Jang JS, Jen J, Li Y, Chanana P, Mansfield AS, Park SS, Markovic SN, Dronca RS, Dong H. CX3CR1 identifies PD-1 therapy-responsive CD8+ T cells that withstand chemotherapy during cancer chemoimmunotherapy. JCI Insight. 2018;3:e97828.CrossRefPubMedPubMedCentral
11.
go back to reference Brierley JD, Gospodarowicz MK, Wittekind C. TNM classification of malignant tumours. Wiley Blackwell; Oxford, UK. 2017 Brierley JD, Gospodarowicz MK, Wittekind C. TNM classification of malignant tumours. Wiley Blackwell; Oxford, UK. 2017
12.
go back to reference Kanda Y. Investigation of the freely available easy-to-use software “EZR” for medical statistics. Bone marrow transplantation. 2013;48:452–8.ADSCrossRefPubMed Kanda Y. Investigation of the freely available easy-to-use software “EZR” for medical statistics. Bone marrow transplantation. 2013;48:452–8.ADSCrossRefPubMed
13.
go back to reference Danger R, Moiteaux Q, Feseha Y, Geffard E, Ramstein G, Brouard S. FaDA: A web application for regular laboratory data analyses. PLoS One. 2021;16:e0261083.CrossRefPubMedPubMedCentral Danger R, Moiteaux Q, Feseha Y, Geffard E, Ramstein G, Brouard S. FaDA: A web application for regular laboratory data analyses. PLoS One. 2021;16:e0261083.CrossRefPubMedPubMedCentral
14.
go back to reference Okabe Y. Immune Niche Within the Peritoneal Cavity. Curr Top Microbiol Immunol. 2021;434:123–34.PubMed Okabe Y. Immune Niche Within the Peritoneal Cavity. Curr Top Microbiol Immunol. 2021;434:123–34.PubMed
15.
go back to reference Schurink B, Cleypool CGJ, Bleys R. A rapid and simple method for visualizing milky spots in large fixed tissue samples of the human greater omentum. Biotech Histochem. 2019;94:429–34.CrossRefPubMed Schurink B, Cleypool CGJ, Bleys R. A rapid and simple method for visualizing milky spots in large fixed tissue samples of the human greater omentum. Biotech Histochem. 2019;94:429–34.CrossRefPubMed
16.
go back to reference Mellor KL, Powell A, Lewis WG. Systematic Review and Meta-Analysis of the Prognostic Significance of Neutrophil-Lymphocyte Ratio (NLR) After R0 Gastrectomy for Cancer. J Gastrointest Cancer. 2018;49:237–44.CrossRefPubMedPubMedCentral Mellor KL, Powell A, Lewis WG. Systematic Review and Meta-Analysis of the Prognostic Significance of Neutrophil-Lymphocyte Ratio (NLR) After R0 Gastrectomy for Cancer. J Gastrointest Cancer. 2018;49:237–44.CrossRefPubMedPubMedCentral
17.
go back to reference Schiefer S, Wirsik NM, Kalkum E, Seide SE, Nienhüser H, Müller B, Billeter A, Büchler MW, Schmidt T, Probst P. Systematic Review of Prognostic Role of Blood Cell Ratios in Patients with Gastric Cancer Undergoing Surgery. Diagnostics (Basel). 2022;12:593.CrossRefPubMedPubMedCentral Schiefer S, Wirsik NM, Kalkum E, Seide SE, Nienhüser H, Müller B, Billeter A, Büchler MW, Schmidt T, Probst P. Systematic Review of Prognostic Role of Blood Cell Ratios in Patients with Gastric Cancer Undergoing Surgery. Diagnostics (Basel). 2022;12:593.CrossRefPubMedPubMedCentral
18.
go back to reference Cupp MA, Cariolou M, Tzoulaki I, Aune D, Evangelou E, Berlanga-Taylor AJ. Neutrophil to lymphocyte ratio and cancer prognosis: an umbrella review of systematic reviews and meta-analyses of observational studies. BMC Med. 2020;18:360.CrossRefPubMedPubMedCentral Cupp MA, Cariolou M, Tzoulaki I, Aune D, Evangelou E, Berlanga-Taylor AJ. Neutrophil to lymphocyte ratio and cancer prognosis: an umbrella review of systematic reviews and meta-analyses of observational studies. BMC Med. 2020;18:360.CrossRefPubMedPubMedCentral
19.
go back to reference Yamamoto T, Kawada K, Obama K. Inflammation-Related Biomarkers for the Prediction of Prognosis in Colorectal Cancer Patients. Int J Mol Sci. 2021;22:8002.CrossRefPubMedPubMedCentral Yamamoto T, Kawada K, Obama K. Inflammation-Related Biomarkers for the Prediction of Prognosis in Colorectal Cancer Patients. Int J Mol Sci. 2021;22:8002.CrossRefPubMedPubMedCentral
20.
21.
go back to reference Yang Y, Li C, Liu T, Dai X, Bazhin AV. Myeloid-Derived Suppressor Cells in Tumors: From Mechanisms to Antigen Specificity and Microenvironmental Regulation. Front Immunol. 2020;11:1371.CrossRefPubMedPubMedCentral Yang Y, Li C, Liu T, Dai X, Bazhin AV. Myeloid-Derived Suppressor Cells in Tumors: From Mechanisms to Antigen Specificity and Microenvironmental Regulation. Front Immunol. 2020;11:1371.CrossRefPubMedPubMedCentral
22.
go back to reference Veglia F, Sanseviero E, Gabrilovich DI. Myeloid-derived suppressor cells in the era of increasing myeloid cell diversity. Nat Rev Immunol. 2021;21(8):485–98 Veglia F, Sanseviero E, Gabrilovich DI. Myeloid-derived suppressor cells in the era of increasing myeloid cell diversity. Nat Rev Immunol. 2021;21(8):485–98
23.
go back to reference Qin R, Ren W, Ya G, Wang B, He J, Ren S, Jiang L, Zhao S. Role of chemokines in the crosstalk between tumor and tumor-associated macrophages. Clin Exp Med. 2023;23(5):1359–73. Qin R, Ren W, Ya G, Wang B, He J, Ren S, Jiang L, Zhao S. Role of chemokines in the crosstalk between tumor and tumor-associated macrophages. Clin Exp Med. 2023;23(5):1359–73.
Metadata
Title
Involvement of CX3CR1+ cells appearing in the abdominal cavity in the immunosuppressive environment immediately after gastric cancer surgery
Authors
Seiji Natsuki
Mami Yoshii
Hiroaki Tanaka
Takuya Mori
Sota Deguchi
Yuichiro Miki
Tatsuro Tamura
Takahiro Toyokawa
Shigeru Lee
Kiyoshi Maeda
Publication date
01-12-2024
Publisher
BioMed Central
Published in
World Journal of Surgical Oncology / Issue 1/2024
Electronic ISSN: 1477-7819
DOI
https://doi.org/10.1186/s12957-024-03353-1

Other articles of this Issue 1/2024

World Journal of Surgical Oncology 1/2024 Go to the issue