Human NKp44+ Group 3 Innate Lymphoid Cells Associate with Tumor-Associated Tertiary Lymphoid Structures in Colorectal Cancer

Atsuyo Ikeda; Takayuki Ogino; Hisako Kayama; Daisuke Okuzaki; Junichi Nishimura; Shiki Fujino; Norikatsu Miyoshi; Hidekazu Takahashi; Mamoru Uemura; Chu Matsuda; Hirofumi Yamamoto; Kiyoshi Takeda; Tsunekazu Mizushima; Masaki Mori; Yuichiro Doki

doi:10.1158/2326-6066.CIR-19-0775

Human NKp44⁺ Group 3 Innate Lymphoid Cells Associate with Tumor-Associated Tertiary Lymphoid Structures in Colorectal Cancer

Cancer Immunol Res. 2020 Jun;8(6):724-731. doi: 10.1158/2326-6066.CIR-19-0775. Epub 2020 Mar 30.

Authors

Atsuyo Ikeda¹, Takayuki Ogino², Hisako Kayama^{3

4

5}, Daisuke Okuzaki⁶, Junichi Nishimura⁷, Shiki Fujino¹, Norikatsu Miyoshi¹, Hidekazu Takahashi¹, Mamoru Uemura¹, Chu Matsuda¹, Hirofumi Yamamoto¹, Kiyoshi Takeda^{8

4}, Tsunekazu Mizushima^{1

9}, Masaki Mori¹⁰, Yuichiro Doki¹

Affiliations

¹ Department of Gastroenterological Surgery, Graduate School of Medicine, Osaka University, Suita, Osaka, Japan.
² Department of Gastroenterological Surgery, Graduate School of Medicine, Osaka University, Suita, Osaka, Japan. togino04@gesurg.med.osaka-u.ac.jp kayama@ongene.med.osaka-u.ac.jp.
³ Laboratory of Immune Regulation, Department of Microbiology and Immunology, Graduate School of Medicine, Osaka University, Suita, Osaka, Japan. togino04@gesurg.med.osaka-u.ac.jp kayama@ongene.med.osaka-u.ac.jp.
⁴ Immunology Frontier Research Center, Osaka University, Suita, Osaka, Japan.
⁵ Institute for Advanced Co-Creation Studies, Osaka University, Suita, Osaka, Japan.
⁶ Genome Information Research Center, Research Institute for Microbial Diseases, Osaka University, Suita, Osaka, Japan.
⁷ Department of Surgery, Osaka International Cancer Institute, Osaka, Japan.
⁸ Laboratory of Immune Regulation, Department of Microbiology and Immunology, Graduate School of Medicine, Osaka University, Suita, Osaka, Japan.
⁹ Department of Therapeutics for Inflammatory Bowel Diseases, Graduate School of Medicine, Osaka University, Suita, Osaka, Japan.
¹⁰ Department of Surgery and Science, Graduate School of Medical Sciences, Kyusyu University, Fukuoka, Japan.

PMID: 32229590
DOI: 10.1158/2326-6066.CIR-19-0775

Abstract

Innate lymphoid cells (ILC) are responsible for mucosal tissue homeostasis and are involved in the progression and suppression of several types of cancer. However, the effects of ILCs on colorectal cancer are poorly understood. We characterized human ILCs in normal colon and colorectal cancer tissue, investigating their role in the tumor immune microenvironment. Normal mucosa and tumor tissues were obtained from patients with colorectal cancer, and the cells were isolated by enzymatic digestion. NKp44⁺ ILC3s with high expression of tertiary lymphoid structure (TLS) formation-related genes, including LTA, LTB, and TNF, accumulated in the normal colonic mucosa and T1/T2 tumors. However, the number of NKp44⁺ ILC3s was significantly reduced in T3/T4 tumors compared with normal colonic mucosa and T1/T2 tumors. NKp44⁺ ILC3s present in T3/T4 tumors had decreased expression of TLS formation-related genes, whereas stromal cells had decreased expression of CXCL13, CCL19, and CCL21 The decreasing number of NKp44⁺ ILC3s during tumor progression correlated with the TLS density in tumors. Thus, our results indicate that NKp44⁺ ILC3s infiltrate colorectal cancer tissue, but the number of cells decreases in T3/T4 tumors with associated decreases in TLS induction.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Colon / immunology*
Colorectal Neoplasms / immunology
Colorectal Neoplasms / pathology*
Humans
Immunity, Innate / immunology*
Lymphocytes / immunology*
Natural Cytotoxicity Triggering Receptor 2 / immunology*
Tertiary Lymphoid Structures / immunology
Tertiary Lymphoid Structures / pathology*
Tumor Cells, Cultured
Tumor Microenvironment / immunology*

Substances

NCR2 protein, human
Natural Cytotoxicity Triggering Receptor 2