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

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

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.

Highlights

Innate lymphoid cells (ILC) are tissue-resident lymphocytes and classified as natural killer (NK) cells, ILC1s, ILC2s, ILC3s, and lymphoid tissue inducer (LTi) cells [1]
We found that the abundance of NKp44þ ILC3s and their expression of tertiary lymphoid structure (TLS) formation– related genes were markedly reduced in T3/T4 tumors
Subset IV and subset V highly expressed RORgt, which is encoded by RORC and responsible for the development of ILC3s, whereas subset III expressed a master regulator of ILC1, T-bet, which is encoded by TBX21

Summary

Introduction

Innate lymphoid cells (ILC) are tissue-resident lymphocytes and classified as natural killer (NK) cells, ILC1s, ILC2s, ILC3s, and lymphoid tissue inducer (LTi) cells [1]. ILC3s that express the transcription factor RORgt and produce IL17 and IL22, are abundant in the intestine and important for host defenses against invading pathogens [2,3,4,5]. ILC3s can regulate the responses of IL17- or IFNg-producing CD4þ T cells to commensal bacteria through antigen presentation via MHC class II. These cells are decreased in pediatric patients with Crohn disease [6]. ILC3s promote regulatory T-cell– mediated oral tolerance by producing IL2 and this ILC3-mediated. Note: Supplementary data for this article are available at Cancer Immunology Research Online (http://cancerimmunolres.aacrjournals.org/).

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