Sexual dimorphism and the role of estrogen in the immune microenvironment of liver metastases

Simon Milette, Masakazu Hashimoto, Stephanie Perrino, Shu Qi, Michely Chen, Boram Ham, Ni Wang, Roman Istomine, Andrew M. Lowy, Ciriaco A. Piccirillo and Pnina Brodt ()
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Simon Milette: McGill University
Masakazu Hashimoto: Cancer Research Program, Research Institute of the McGill University Health Centre, Glen Site
Stephanie Perrino: Cancer Research Program, Research Institute of the McGill University Health Centre, Glen Site
Shu Qi: Cancer Research Program, Research Institute of the McGill University Health Centre, Glen Site
Michely Chen: McGill University
Boram Ham: McGill University
Ni Wang: Cancer Research Program, Research Institute of the McGill University Health Centre, Glen Site
Roman Istomine: McGill University
Andrew M. Lowy: Division of Surgical Oncology, Department of Surgery, Moores Cancer Centre at UC San Diego Health
Ciriaco A. Piccirillo: McGill University
Pnina Brodt: McGill University

Nature Communications, 2019, vol. 10, issue 1, 1-16

Abstract: Abstract Liver metastases (LM) remain a major cause of cancer-associated death and a clinical challenge. Here we explore a sexual dimorphism observed in the regulation of the tumor immune microenvironment (TIME) of LM, wherein the accumulation of myeloid-derived suppressor cells (MDSC) and regulatory T cells in colon and lung carcinoma LM is TNFR2-dependent in female, but not in male mice. In ovariectomized mice, a marked reduction is observed in colorectal, lung and pancreatic carcinoma LM that is reversible by estradiol reconstitution. This is associated with reduced liver MDSC accumulation, increased interferon-gamma (IFN-γ) and granzyme B production in CD8+ T cells and reduced TNFR2, IDO2, TDO and Serpin B9 expression levels. Treatment with tamoxifen increases liver cytotoxic T cell accumulation and reduces colon cancer LM. The results identify estrogen as a regulator of a pro-metastatic immune microenvironment in the liver and a potential target in the management of liver metastatic disease.

Date: 2019
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DOI: 10.1038/s41467-019-13571-x

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