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.
Highlights
Liver metastases (LM) remain a major cause of cancer-associated death and a clinical challenge
We previously reported that in female mice, TNF receptor 2 (TNFR2) plays a critical role in colorectal LM by regulating myeloid-derived suppressor cells (MDSC) and Treg accumulation in the liver[1]
When LM was evaluated in male mice, following inoculation of age-matched TNFR2-null mice of the same cohort with colon carcinoma MC-38 cells via the intrasplenic/portal route, we found that the numbers of hepatic metastases in these mice did not significantly differ from those in WT controls
Summary
Liver metastases (LM) remain a major cause of cancer-associated death and a clinical challenge. 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. 2 Cancer Research Program, Research Institute of the McGill University Health Centre, Glen Site, 1001 Décarie Blvd, Montréal, QC H4A 3J1, Canada. 8 Program in Infectious Disease and Immunity in Global Health, Research Institute of the McGill University Health Centre, Glen Site, 1001 Décarie Blvd, Montréal, QC H4A 3J1, Canada. In TNFR2-null female mice, the incidence of LM was significantly reduced and this was associated with a significant decrease in the accumulation of myeloid-derived suppressor cells (MDSC) and CD4+CD25+Foxp3+ regulatory. The mechanisms whereby sex differences affect disease outcome appear to be multifactorial and complex, and remain incompletely understood
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