Characteristics and Clinical Significance of Immune Cells in Omental Milky Spots of Patients with Gastric Cancer

Overview

Journal Front Immunol

Specialty Allergy & Immunology

Date 2025 Feb 14

PMID 39949777

Authors

Yasunobu Mano

Yuka Igarashi

Keisuke Komori

Itaru Hashimoto

Hayato Watanabe

Kosuke Takahashi

Kazuki Kano

Hirohito Fujikawa

Takanobu Yamada

Hidetomo Himuro

Taku Kouro

Feifei Wei

Kayoko Tsuji

Shun Horaguchi

Mitsuru Komahashi

Takashi Oshima

Tetsuro Sasada

Affiliations

Soon will be listed here.

Abstract

The omentum is a common site of peritoneal metastasis in various cancers, including gastric cancer. It contains immune cell aggregates known as milky spots, which provide a microenvironment for peritoneal immunity by regulating innate and adaptive immune responses. In this study, we investigated gene expression profiles in cells from omental milky spots of patients with gastric cancer (n = 37) by RNA sequencing analysis and classified the patients into four groups (G1-4). Notably, significant differences were observed between the groups in terms of macroscopic type, lymphatic invasion, venous invasion, and pathological stage (pStage). G3, which was enriched in genes related to acquired immunity, showed earlier tumor stages (macroscopic type 0, Ly0, V0, and pStage I) and a better prognosis. In contrast, G4 showed enrichment of genes related to neutrophils and innate immunity; G1 and G2 showed no enrichment of innate or adaptive immune-related genes, suggesting an immune desert microenvironment. Cytometric analysis revealed significantly more T and B cells and fewer neutrophils in G3. Accordingly, the immune microenvironment in omental milky spots may vary depending on the stage of gastric cancer progression. When univariate Cox proportional hazards regression models were used to search for prognostically relevant genes specific to G3, 23 potential prognostic genes were identified as common genes associated with relapse-free survival and overall survival. In addition, the multivariate Cox proportional hazards model using these prognostic genes and clinicopathological information showed that combining the B cell marker and Ly had a high predictive accuracy for prognosis. Based on this study's results, it is possible that tumor progression, such as lymphatic and/or venous infiltration of tumor cells, may affect the immune cell composition and proportions in omental milky spots of patients with gastric cancer and analysis of gene expression in omental milky spots may help to predict gastric cancer prognosis.

References

Yoshihara T, Okabe Y . Aldh1a2 + fibroblastic reticular cells regulate lymphocyte recruitment in omental milky spots. J Exp Med. 2023; 220(5). PMC: 9997506. DOI: 10.1084/jem.20221813. View

Chen S, Zhou Y, Chen Y, Gu J . fastp: an ultra-fast all-in-one FASTQ preprocessor. Bioinformatics. 2018; 34(17):i884-i890. PMC: 6129281. DOI: 10.1093/bioinformatics/bty560. View

Koemans W, Lurvink R, Grootscholten C, Verhoeven R, de Hingh I, van Sandick J . Synchronous peritoneal metastases of gastric cancer origin: incidence, treatment and survival of a nationwide Dutch cohort. Gastric Cancer. 2021; 24(4):800-809. DOI: 10.1007/s10120-021-01160-1. View

Li B, Dewey C . RSEM: accurate transcript quantification from RNA-Seq data with or without a reference genome. BMC Bioinformatics. 2011; 12:323. PMC: 3163565. DOI: 10.1186/1471-2105-12-323. View

Becht E, Giraldo N, Lacroix L, Buttard B, Elarouci N, Petitprez F . Estimating the population abundance of tissue-infiltrating immune and stromal cell populations using gene expression. Genome Biol. 2016; 17(1):218. PMC: 5073889. DOI: 10.1186/s13059-016-1070-5. View

Monaco G, Lee B, Xu W, Mustafah S, Hwang Y, Carre C . RNA-Seq Signatures Normalized by mRNA Abundance Allow Absolute Deconvolution of Human Immune Cell Types. Cell Rep. 2019; 26(6):1627-1640.e7. PMC: 6367568. DOI: 10.1016/j.celrep.2019.01.041. View

Chang K, Pastan I . Molecular cloning of mesothelin, a differentiation antigen present on mesothelium, mesotheliomas, and ovarian cancers. Proc Natl Acad Sci U S A. 1996; 93(1):136-40. PMC: 40193. DOI: 10.1073/pnas.93.1.136. View

Gillette M, Satpathy S, Cao S, Dhanasekaran S, Vasaikar S, Krug K . Proteogenomic Characterization Reveals Therapeutic Vulnerabilities in Lung Adenocarcinoma. Cell. 2020; 182(1):200-225.e35. PMC: 7373300. DOI: 10.1016/j.cell.2020.06.013. View

Newman A, Steen C, Liu C, Gentles A, Chaudhuri A, Scherer F . Determining cell type abundance and expression from bulk tissues with digital cytometry. Nat Biotechnol. 2019; 37(7):773-782. PMC: 6610714. DOI: 10.1038/s41587-019-0114-2. View

10.

Shafi A, McNair C, McCann J, Alshalalfa M, Shostak A, Severson T . The circadian cryptochrome, CRY1, is a pro-tumorigenic factor that rhythmically modulates DNA repair. Nat Commun. 2021; 12(1):401. PMC: 7810852. DOI: 10.1038/s41467-020-20513-5. View

11.

Uemura N, Okamoto S, Yamamoto S, Matsumura N, Yamaguchi S, Yamakido M . Helicobacter pylori infection and the development of gastric cancer. N Engl J Med. 2001; 345(11):784-9. DOI: 10.1056/NEJMoa001999. View

12.

Thomassen I, van Gestel Y, van Ramshorst B, Luyer M, Bosscha K, Nienhuijs S . Peritoneal carcinomatosis of gastric origin: a population-based study on incidence, survival and risk factors. Int J Cancer. 2013; 134(3):622-8. DOI: 10.1002/ijc.28373. View

13.

Norreen-Thorsen M, Struck E, Oling S, Zwahlen M, Von Feilitzen K, Odeberg J . A human adipose tissue cell-type transcriptome atlas. Cell Rep. 2022; 40(2):111046. DOI: 10.1016/j.celrep.2022.111046. View

14.

Cao L, Hu X, Zhang J, Huang G, Zhang Y . The role of the CCL22-CCR4 axis in the metastasis of gastric cancer cells into omental milky spots. J Transl Med. 2014; 12:267. PMC: 4177767. DOI: 10.1186/s12967-014-0267-1. View

15.

de Hoon M, Imoto S, Nolan J, Miyano S . Open source clustering software. Bioinformatics. 2004; 20(9):1453-4. DOI: 10.1093/bioinformatics/bth078. View

16.

Guinney J, Dienstmann R, Wang X, De Reynies A, Schlicker A, Soneson C . The consensus molecular subtypes of colorectal cancer. Nat Med. 2015; 21(11):1350-6. PMC: 4636487. DOI: 10.1038/nm.3967. View

17.

Fujikawa H, Koumori K, Watanabe H, Kano K, Shimoda Y, Aoyama T . The Clinical Significance of Lymphovascular Invasion in Gastric Cancer. In Vivo. 2020; 34(3):1533-1539. PMC: 7279808. DOI: 10.21873/invivo.11942. View

18.

Shimotsuma M, Kawata M, Hagiwara A, Takahashi T . Milky spots in the human greater omentum. Macroscopic and histological identification. Acta Anat (Basel). 1989; 136(3):211-6. DOI: 10.1159/000146888. View

19.

Nieman K, Romero I, Van Houten B, Lengyel E . Adipose tissue and adipocytes support tumorigenesis and metastasis. Biochim Biophys Acta. 2013; 1831(10):1533-41. PMC: 3742583. DOI: 10.1016/j.bbalip.2013.02.010. View

20.

Liu J, Geng X, Li Y . Milky spots: omental functional units and hotbeds for peritoneal cancer metastasis. Tumour Biol. 2016; 37(5):5715-26. PMC: 4875158. DOI: 10.1007/s13277-016-4887-3. View