Single Cell Mass Cytometry Revealed the Immunomodulatory Effect of Cisplatin Via Downregulation of Splenic CD44+, IL-17A+ MDSCs and Promotion of Circulating IFN-γ+ Myeloid Cells in the 4T1 Metastatic Breast Cancer Model.

József Á Balog,Anita K Kovács,Lajos I Nagy,László Hackler Jr,László G Puskás,Róbert Alföldi,Gábor J Szebeni,Patrícia Neuperger

doi:10.3390/ijms21010170

József Á Balog, Anita K Kovács + Show 6 more

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https://doi.org/10.3390/ijms21010170

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Abstract

The treatment of metastatic breast cancer remained a challenge despite the recent breakthrough in the immunotherapy regimens. Here, we addressed the multidimensional immunophenotyping of 4T1 metastatic breast cancer by the state-of-the-art single cell mass cytometry (CyTOF). We determined the dose and time dependent cytotoxicity of cisplatin on 4T1 cells by the xCelligence real-time electronic sensing assay. Cisplatin treatment reduced tumor growth, number of lung metastasis, and the splenomegaly of 4T1 tumor bearing mice. We showed that cisplatin inhibited the tumor stroma formation, the polarization of carcinoma-associated fibroblasts by the diminished proteolytic activity of fibroblast activating protein. The CyTOF analysis revealed the emergence of CD11b+/Gr-1+/CD44+ or CD11b+/Gr-1+/IL-17A+ myeloid-derived suppressor cells (MDSCs) and the absence of B220+ or CD62L+ B-cells, the CD62L+/CD4+ and CD62L+/CD8+ T-cells in the spleen of advanced cancer. We could show the immunomodulatory effect of cisplatin via the suppression of splenic MDSCs and via the promotion of peripheral IFN-γ+ myeloid cells. Our data could support the use of low dose chemotherapy with cisplatin as an immunomodulatory agent for metastatic triple negative breast cancer.

Highlights

The role of the tumor microenvironment, the interaction of cancer cells with the extracellular matrix, endothelial cells, cancer-associated fibroblasts, and leukocytes in the tumor stroma have been increasingly considered as a milestone in cancer development, especially in the last decade [1,2]
We have previously reviewed how cancer-related chronic inflammation can lead to the generation of immature myeloid-derived suppressor cells (MDSCs) and to the alternative polarization of tumor-associated macrophages (TAMs) [12], which manifests autonomously in the 4T1 breast cancer model [13,14]
Our findings showed that cisplatin treatment reduced tumor growth, number of lung metastasis and the splenomegaly of 4T1 tumor bearing mice

Summary

Introduction

The role of the tumor microenvironment, the interaction of cancer cells with the extracellular matrix, endothelial cells, cancer-associated fibroblasts, and leukocytes in the tumor stroma have been increasingly considered as a milestone in cancer development, especially in the last decade [1,2]. The 4T1 model is among the few murine triple negative breast cancer (TNBC) models that spontaneously metastasize to sites affected in human breast cancer (e.g., lung) in an immunocompetent host [7]. Orthotopic transplantation of 4T1 cells offers a relevant tumor model to study efficacy of drug candidates or immune therapy regimens [8]. We showed the tumor promoting effect of mesenchymal stem cell (cancer associated fibroblast)-derived galectin-1 in the 4T1 model [9], and later on we screened an anti-cancer compound library of imidazo[1-2-b]pyrazole-7-carboxamides in both two- and three-dimensional cell cultures of 4T1 cells [10,11]

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