Resident stroma-secreted chemokine CCL2 governs myeloid-derived suppressor cells in the tumor microenvironment

Abstract

Accumulating evidence has shown that cancer stroma and bone marrow-derived cells (BMDCs) in the tumor microenvironment (TME) play vital roles in tumor progression. However, the mechanism by which oral cancer stroma recruits any particular subset of BMDCs remains largely unknown. Here we sought to identify the subset of BMDCs that is recruited by cancer stroma. We established a sequential transplantation model in BALB/c nude mice, including (i) bone marrow transplantation of GFP-expressing cells and (ii) co-xenografting of patient-derived stroma (two cases, designated PDS1 and PDS2) with oral cancer cells (HSC-2). As controls, xenografting was performed with HSC-2 alone or in combination with normal human dermal fibroblasts (HDF). PDS1, PDS2, and HDF all promoted BMDCs migration in vitro and recruitment in vivo. Multicolor immunofluorescence revealed that the PDS co-xenografts recruited Arginase-1/CD11b/GR1/GFP quadruple-positive cells, which are myeloid-derived suppressor cells (MDSCs), to the TME, whereas the HDF co-xenograft did not.Screening using microarrays revealed that PDS1 and PDS2 expressed CCL2 mRNA (encoding C-C motif chemokine ligand 2) at higher levels than did HDF. Indeed, PDS xenografts contained significantly higher proportions of CCL2-positive stromal cells and CCR2/Arginase-1/CD11b/GR1 quadruple-positive MDSCs (as receiver cells) than the HDF co-xenograft. Consistently, a CCL2 synthesis inhibitor and a CCR2 antagonist significantly inhibited the PDS-driven migration of BM cells in vitro. Furthermore, intraperitoneal injection of the CCR2 antagonist to the PDS xenograft models significantly reduced the CCR2/Arginase-1/CD11b/GR1 quadruple-positive MDSCs infiltration to the TME. In conclusion, oral cancer stroma-secreted CCL2 is a key signal for recruiting CCR2-positive MDSCs from bone marrow to the TME.

Tumor-educated Gr1+CD11b+cells instigate breast cancer metastasis by twisting cancer cells plasticity via OSM/IL6–JAK signaling

“…Recruitment and accumulation of Gr1 + CD11b + cells in the TME, particularly through the chemokines CCL2, CXCL1 and CXCL2, or IL-33, is considered a critical step for their contribution to tumor progression and metastasis (67)(68)(69)(70). Consistent with these observations, tumors derived from sorted 4T1-Sca-1 + cells, or MR13 cells that are intrinsically enriched for Sca-1 + cells, have a higher content of Gr1 high CD11b + Ly6C low cells compared to tumors derived from 4T1-Sca-1or parental 4T1 cells, respectively (Figure 2A and 5K).…”

SOD3 Expression in Tumor Stroma Provides the Tumor Vessel Maturity in Oral Squamous Cell Carcinoma

“…Western blotting was performed as described previously [ 7 ]. 5 μg protein mixed with 4× Laemmli sample buffer (Bio-Rad Laboratories, Hercules, CA, USA) was boiled at 95 °C for 5 min.…”

“…It has been reported that a higher proportion of stroma in OSCC relates to poor prognosis [ 4 , 5 ]. We also observed that incorporating different stromal cells into oral cancer xenograft models showed different effects on tumor progression, bone invasion, and bone marrow cell recruitment [ 6 , 7 ]. On the other hand, tumor angiogenesis supports tumor development, dissemination, and metastasis [ 8 ].…”

Strategies to overcome myeloid cell induced immune suppression in the tumor microenvironment

“…Many tumors secrete large amounts of CCL2, thereby recruiting circulating inflammatory monocytes into tumor tissues where they then differentiate into M2 TAMs ( 32 , 117 , 118 ). CCL2 may also play a minor role in PMN-MDSC recruitment, though the primary chemokine driving TAN recruitment is CXCL8 ( 119 ). There have been numerous preclinical studies in rodent models assessing inhibitors of the CCL2-CCR2 axis using either small molecule CCL2 inhibitors or monoclonal antibodies, and most have demonstrated inhibition of tumor growth and/or decreased metastatic burden ( 120 ).…”