Mouse Breast Carcinoma Monocytic/Macrophagic Myeloid-Derived Suppressor Cell Infiltration as a Consequence of Endothelial Dysfunction in Shb-Deficient Endothelial Cells Increases Tumor Lung Metastasis

Abstract

Metastasis reflects both the inherent properties of tumor cells and the response of the stroma to the presence of the tumor. Vascular barrier properties, either due to endothelial cell (EC) or pericyte function, play an important role in metastasis in addition to the contribution of the immune system. The Shb gene encodes the Src homology-2 domain protein B that operates downstream of tyrosine kinases in both vascular and immune cells. We have investigated E0771.lmb breast carcinoma metastasis in mice with conditional deletion of the Shb gene using the Cdh5-CreERt2 transgene, resulting in inactivation of the Shb-gene in EC and some hematopoietic cell populations. Lung metastasis from orthotopic tumors, tumor vascular and immune cell characteristics, and immune cell gene expression profiles were determined. We found no increase in vascular leakage that could explain the observed increase in metastasis upon the loss of Shb expression. Instead, Shb deficiency in EC promoted the recruitment of monocytic/macrophagic myeloid-derived suppressor cells (mMDSC), an immune cell type that confers a suppressive immune response, thus enhancing lung metastasis. An MDSC-promoting cytokine/chemokine profile was simultaneously observed in tumors grown in mice with EC-specific Shb deficiency, providing an explanation for the expanded mMDSC population. The results demonstrate an intricate interplay between tumor EC and immune cells that pivots between pro-tumoral and anti-tumoral properties, depending on relevant genetic and/or environmental factors operating in the microenvironment.

Perspectives on Vascular Regulation of Mechanisms Controlling Selective Immune Cell Function in the Tumor Immune Response

“…Monocytic/macrophagic MDSC infiltration into breast carcinoma tumors was increased in mice exhibiting Shb deficiency in EC [45], an effect that correlated with increased metastasis. In that study, an EC gatekeeping function was likely to be altered in such a manner that an IC population promoting recruitment and expansion of MDSC was specifically allowed to transmigrate over the vascular barrier.…”

“…The EC-specific Shb gene knockout confers altered EC properties that result in increased hypoxia in B16F10 melanoma tumors [48]. Whereas hypoxia was not investigated in a model of breast carcinoma metastasis grown in mice with Shb-deficient EC, increased hypoxia is a potential explanation for the augmented recruitment of MDSC observed in that setting [45]. Similarly, Sorafenib (multi-kinase inhibitor) treatment of hepatocellular carcinomas causes hypoxia that recruits immunosuppressive cells [80], including Tregs and M2 macrophages.…”

Endothelial cells in tumor microenvironment: insights and perspectives

“…Also, NO in the tumor microenvironment inhibits immune cell recruitment ( 55 ). Shb deprivation in tumor-associated ECs enhances the recruitment of myeloid-derived suppressor cells (MDSCs) that confer a suppressive immune response, thus promoting tumor metastasis ( 56 ) ( Figure 1A ).…”

Exploring the crosstalk between endothelial cells, immune cells, and immune checkpoints in the tumor microenvironment: new insights and therapeutic implications

“…Myeloid-derived suppressor cells (MDSCs), notorious for their potent immunosuppressive properties [ 141 ], play crucial roles in tumor angiogenesis, drug resistance, and metastasis [ 142 ]. Notably, TEC-specific Shb deprivation enhances MDSC recruitment and facilitates breast cancer transmission to the lungs in mice [ 143 ].…”