Distinct populations of metastases-enabling myeloid cells expand in the liver of mice harboring invasive and preinvasive intra-abdominal tumor

Abstract

The liver is the most common site of adenocarcinoma metastases, even in patients who initially present with early disease. We postulated that immune-suppressive cells in the liver of tumor-bearing hosts inhibit anti-tumor T cells, thereby accelerating the growth of liver metastases. Using models of early preinvasive pancreatic neoplasia and advanced colorectal cancer, aims of this study were to determine immune phenotype, stimulus for recruitment, inhibitory effects, and tumor-enabling function of immune-suppressive cells in the liver of tumor-bearing hosts. We found that in mice with intra-abdominal malignancies, two distinct CD11b(+)Gr1(+) populations with divergent phenotypic and functional properties accumulate in the liver, becoming the dominant hepatic leukocytes. Their expansion is contingent on tumor expression of KC. These cells are distinct from CD11b(+)Gr1(+) populations in other tissues of tumor-bearing hosts in terms of cellular phenotype and cytokine and chemokine profile. Liver CD11b(+)Gr1(+) cells are highly suppressive of T cell activation, proliferation, and cytotoxicity and induce the development of Tregs. Moreover, liver myeloid-derived suppressor cells accelerate the development of hepatic metastases by inactivation of cytotoxic T cells. These findings may explain the propensity of patients with intra-abdominal cancers to develop liver metastases and suggest a promising target for experimental therapeutics.

Haematopoietic focal adhesion kinase deficiency alters haematopoietic homeostasis to drive tumour metastasis

“…Since no changes in CLP were observed in the bone marrow ( Supplementary Fig. 8B), it is possible that these T cell changes are a consequence of the increased Gr1 þ cell numbers as the latter have been shown previously to have immune suppressive properties 23,24 . Metastasis and neutrophil recruitment are dependent on complex cytokine networks.…”

“…Granulocytic and monocytic CD11b þ Gr1 þ cells are also referred to as MDSCs. MDSCs are characterized by their ability to suppress CD8 and CD4 T cell proliferation and cytotoxicity and suppress NK cell activity, which, together, are thought to enhance metastasis 23,24 . Moreover C5/C5a has been shown not only to increase the infiltration of MDSCs, but also their immune suppressive properties, resulting in decreased infiltration of CD8 T cells in tumours 66 .…”

“…MDSCs are a mixture of myeloid cells with characteristics of monocytes and granulocytes and are generally described by the co-expression of the mouse markers CD11b and Gr1 (CD11b þ Gr1 þ ) 21,22 . Their expansion at metastatic sites generates an immunosuppressive niche that suppresses T cell activation, proliferation and cytotoxicity and also suppresses NK cell cytotoxicity [23][24][25][26] . These cells have been shown to facilitate tumour cell seeding and colonization at metastatic sites and are thereby thought to drive metastasis [27][28][29] .…”

Tumor Microenvironment and Myeloid-Derived Suppressor Cells

“…The PGE2-driven production of CCL2, CXCL8 (also known as IL-8), and CXCL12 has been reported to induce the MDSC accumulation in ovarian and gastric cancer microenvironment [83,84]. Other groups underlined a critical role of CXCL-1, CCL5 and CCL7 in the MDSC accumulation in colon and liver tumor lesions [85,86]. Investigating numerous transplantable tumor mouse models, Sawanobori et al [87] were able to state that the migration of distinct MDSC subsets into the tumor microenvironment was mediated by different chemokines.…”

Toll-like receptor 7 regulates pancreatic carcinogenesis in mice and humans

“…Cell surface marker analysis was performed by flow cytometry using the FACS Calibur (Beckman Coulter) after incubating 5 × 10 5 cells with 1 μg of anti-FcγRIII/II antibody (2.4G2, Fc block; Monoclonal Antibody Core Facility, SloanKettering Institute) and then labeling with 1 μg of FITC-, PE-, PerCP-, or APC-conjugated antibodies directed against B220 (RA3-6B2), CD3ε (17A2), CD4 (RM4-5), CD8α (53-6.7), CD11b (M1/70), CD11c (HL3), CD19 (1D3), CD34 (4H11), CD45 (30-F11), CD133 (315-2C11), CD146 (P1H12), F4/80 (BM8), and Gr1 (RB6-8C5) (all eBiosciences or BioLegend). Gating strategies for leukocyte subsets was as described previously (67)(68)(69). To determine TLR7 expression, cells were fixed, permeabilized, and stained using an mAb directed against TLR7 (IMG-581A; Imgenex).…”