Taisuke Yagi1, Yoshifumi Baba1, Kazuo Okadome1, Yuki Kiyozumi1, Yukiharu Hiyoshi1, Takatsugu Ishimoto1, Masaaki Iwatsuki1, Yuji Miyamoto1, Naoya Yoshida1, Masayuki Watanabe2, Yoshihiro Komohara3, Hideo Baba4. 1. Department of Gastroenterological Surgery, Graduate School of Medical Sciences, Kumamoto University, 1-1-1 Honjo, Chuo-ku, Kumamoto 860-8556, Japan. 2. Department of Gastroenterological Surgery, Cancer Institute Hospital, Japanese Foundation for Cancer Research, 3-8-31 Ariake, Koto-ku, Tokyo 135-8550, Japan. 3. Department of Cell Pathology, Graduate School of Medical Sciences, Faculty of Life Sciences, Kumamoto University, 1-1-1 Honjo, Chuo-ku, Kumamoto 860-8556, Japan. 4. Department of Gastroenterological Surgery, Graduate School of Medical Sciences, Kumamoto University, 1-1-1 Honjo, Chuo-ku, Kumamoto 860-8556, Japan. Electronic address: hdobaba@kumamoto-u.ac.jp.
Abstract
INTRODUCTION: Tumour-associated macrophages (TAMs) in tumour microenvironments promote cancer cell proliferation, immunosuppression and angiogenesis, leading to tumour growth and metastasis. TAMs have become increasingly recognised as a cancer therapy target, such as in combination therapy with an immunity checkpoint inhibitor. However, the clinical and prognostic features of TAMs, and the relationship between TAMs and programmed death ligand 1 (PD-L1), remain unexplored in oesophageal cancer. METHODS: Using a non-biased database of 305 resected oesophageal cancer preparations, we evaluated the expression of two M2-like macrophage markers (CD163 and CD204) and PD-L1 on tumour cells by immunostaining. Through in vitro assays, we examined how TAMs influence phenotypic malignancy and PD-L1 expression. RESULTS: High density of CD163 (n = 160) or CD204 (n = 146) was associated with significantly worse overall survival than low expression (log rank P = 0.0025 and 0.018 for CD163 and CD204, respectively). The prognostic effect of TAMs was not significantly modified by any clinical factors (P > 0.05 for all interactions). High TAM density was significantly associated with increased PD-L1 expression. In in vitro assays, cell invasion and migration ability were significantly more upregulated in oesophageal cancer cell lines cocultured with activated macrophages than in control cell lines. Coculture with activated macrophages elevated the PD-L1 expression in cancer cells. CONCLUSIONS: High TAM density in oesophageal cancer tissues was associated with shorter survival, suggesting a prognostic biomarker role for TAMs. TAMs also increase PD-L1 expression in tumour cells. Given the significant interest in cancer immunotherapies targeting TAMs and PD-L1, the current findings should have considerable clinical implications.
INTRODUCTION:Tumour-associated macrophages (TAMs) in tumour microenvironments promote cancer cell proliferation, immunosuppression and angiogenesis, leading to tumour growth and metastasis. TAMs have become increasingly recognised as a cancer therapy target, such as in combination therapy with an immunity checkpoint inhibitor. However, the clinical and prognostic features of TAMs, and the relationship between TAMs and programmed death ligand 1 (PD-L1), remain unexplored in oesophageal cancer. METHODS: Using a non-biased database of 305 resected oesophageal cancer preparations, we evaluated the expression of two M2-like macrophage markers (CD163 and CD204) and PD-L1 on tumour cells by immunostaining. Through in vitro assays, we examined how TAMs influence phenotypic malignancy and PD-L1 expression. RESULTS: High density of CD163 (n = 160) or CD204 (n = 146) was associated with significantly worse overall survival than low expression (log rank P = 0.0025 and 0.018 for CD163 and CD204, respectively). The prognostic effect of TAMs was not significantly modified by any clinical factors (P > 0.05 for all interactions). High TAM density was significantly associated with increased PD-L1 expression. In in vitro assays, cell invasion and migration ability were significantly more upregulated in oesophageal cancer cell lines cocultured with activated macrophages than in control cell lines. Coculture with activated macrophages elevated the PD-L1 expression in cancer cells. CONCLUSIONS: High TAM density in oesophageal cancer tissues was associated with shorter survival, suggesting a prognostic biomarker role for TAMs. TAMs also increase PD-L1 expression in tumour cells. Given the significant interest in cancer immunotherapies targeting TAMs and PD-L1, the current findings should have considerable clinical implications.
Authors: Maria Davern; Noel E Donlon; Margaret R Dunne; Robert Power; Conall Hayes; Ross King; John V Reynolds Journal: Br J Cancer Date: 2021-04-26 Impact factor: 7.640
Authors: Javier Mora; Christina Mertens; Julia K Meier; Dominik C Fuhrmann; Bernhard Brüne; Michaela Jung Journal: Cells Date: 2019-05-11 Impact factor: 6.600