Myeloid-derived suppressor cells are implicated in regulating permissiveness for tumor metastasis during mouse gestation
Laetitia A. Mauti, … , Paolo Provero, Ivan Stamenkovic
Laetitia A. Mauti, … , Paolo Provero, Ivan Stamenkovic
Published July 1, 2011; First published June 6, 2011
Citation Information: J Clin Invest. 2011;121(7):2794-2807. https://doi.org/10.1172/JCI41936.
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Research Article Oncology

Myeloid-derived suppressor cells are implicated in regulating permissiveness for tumor metastasis during mouse gestation

Abstract

Metastasis depends on the ability of tumor cells to establish a relationship with the newly seeded tissue that is conducive to their survival and proliferation. However, the factors that render tissues permissive for metastatic tumor growth have yet to be fully elucidated. Breast tumors arising during pregnancy display early metastatic proclivity, raising the possibility that pregnancy may constitute a physiological condition of permissiveness for tumor dissemination. Here we have shown that during murine gestation, metastasis is enhanced regardless of tumor type, and that decreased NK cell activity is responsible for the observed increase in experimental metastasis. Gene expression changes in pregnant mouse lung and liver were shown to be similar to those detected in premetastatic sites and indicative of myeloid cell infiltration. Indeed, myeloid-derived suppressor cells (MDSCs) accumulated in pregnant mice and exerted an inhibitory effect on NK cell activity, providing a candidate mechanism for the enhanced metastatic tumor growth observed in gestant mice. Although the functions of MDSCs are not yet understood in the context of pregnancy, our observations suggest that they may represent a shared mechanism of immune suppression occurring during gestation and tumor growth.

Authors

Laetitia A. Mauti, Marie-Aude Le Bitoux, Karine Baumer, Jean-Christophe Stehle, Dela Golshayan, Paolo Provero, Ivan Stamenkovic

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Figure 5

Quantitative and qualitative changes in NK cells are responsible for increased metastatic spread of tumors in 16-day pregnant versus virgin NOD/SCID mice.

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Quantitative and qualitative changes in NK cells are responsible for inc...
(A) Representative FACS images of NK cell quantification in splenocytes (CD49b+NKG2D+ in forward scatter/side scatter leukocyte gate). (B) Quantification of NK cells in blood and spleen by FACS analysis for CD49b+NKG2D+ cells. *P < 0.05, **P < 0.01. (C) Quantification of NK cells in lung and liver single-cell suspensions by FACS analysis for CD49b+NKp46+ cells among CD45+ cells. (D and E) Control (rabbit IgG; rb IgG), NK-depleted (AAGM1), sublethally irradiated (2.7–3.0 Gy), and cg KO NOD/SCID mice were subjected to NK cell quantification in tail vein blood prior to tail vein injection of 1 × 105 luciferase-expressing B16.F10 tumor cells. Shown are (D) absolute NK numbers in tail vein blood by FACS analysis and total leukocyte counting prior to tumor cell injection and (E) bioluminescence imaging. Data are from 6–10 mice per condition. *P < 0.05, ***P < 0.001. (F and G) Tail vein injection of 1 × 105 luciferase-expressing HT1080 (F) and MDA-MB-435 (G) tumor cells into cg KO NOD/SCID mice and bioluminescence imaging. (H) Standard 4-hour 51Cr release cytotoxicity assay with splenocytes extracted from poly(I:C)-stimulated pregnant and virgin NOD/SCID mice and Yac-1 target cells. Graph was adjusted for NK proportions in splenocytes, as determined by flow cytometry. 4 mice were used per condition.