A Mature Tertiary Lymphoid Structure with a Ki-67-Positive Proliferating Germinal Center Is Associated with a Good Prognosis and High Intratumoral Immune Cell Infiltration in Advanced Colorectal Cancer

Author:

Mori Natsumi1,Dorjkhorloo Gendensuren1,Shiraishi Takuya1,Erkhem-Ochir Bilguun2ORCID,Okami Haruka1,Yamaguchi Arisa1,Shioi Ikuma1ORCID,Komine Chika1,Endo Mizuki1,Seki Takaomi1ORCID,Hosoi Nobuhiro1ORCID,Nakazawa Nobuhiro1ORCID,Shibasaki Yuta1,Okada Takuhisa1,Osone Katsuya1,Sano Akihiko1,Sakai Makoto1,Sohda Makoto1,Yokobori Takehiko2ORCID,Shirabe Ken1,Saeki Hiroshi1

Affiliation:

1. Department of General Surgical Science, Graduate School of Medicine, Gunma University, Maebashi 371-8511, Japan

2. Division of Gene Therapy Science, Gunma University Initiative for Advanced Research (GIAR), Maebashi 371-8511, Japan

Abstract

Tertiary lymphoid structures (TLSs) are complex lymphocyte clusters that arise in non-lymphoid tissues due to inflammation or cancer. A mature TLS with proliferating germinal centers is associated with a favorable prognosis in various cancers. However, the effect of TLS maturity on advanced colorectal cancer (CRC) remains unexplored. We analyzed the significance of TLS maturity and tumor Ki-67 expression in surgically resected tumors from 78 patients with pathological T4 CRC. Mature TLS was defined as the organized infiltration of T and B cells with Ki-67-positive proliferating germinal centers. We analyzed the relationship between TLS maturity and intratumoral immune cell infiltration. Mature TLS with germinal center Ki-67 expression was associated with microsatellite instability and improved survival; however, high tumor Ki-67 expression was associated with poor survival in the same cohort. Multivariate analysis identified the absence of mature TLS as an independent predictor of poor post-recurrence overall survival. Intratumoral infiltration of T lymphocytes and macrophages was significantly elevated in tumors with mature TLS compared to those lacking it. High Ki-67 levels and absent mature TLS were identified as poor prognostic factors in advanced CRC. Mature TLS could serve as a promising marker for patients at high-risk of CRC.

Funder

Grants-in-Aid for Scientific Research from the Japan Society for the Promotion of Science

Publisher

MDPI AG

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