Loss of SMAD4 Promotes Colorectal Cancer Progression by Accumulation of Myeloid-Derived Suppressor Cells through the CCL15–CCR1 Chemokine Axis

Inamoto, Susumu; Itatani, Yoshiro; Yamamoto, Takamasa; Minamiguchi, Sachiko; Hirai, Hideyo; Iwamoto, Masayoshi; Hasegawa, Suguru; Taketo, Makoto Mark; Sakai, Yoshiharu; Kawada, Kenji

doi:10.1158/1078-0432.ccr-15-0726

Cited by 108 publications

(100 citation statements)

References 28 publications

(41 reference statements)

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“…(B) J774M cells were treated with IFNg for 24 h and lysed for nuclear extract preparation. The nuclear extracts were incubated with that MDSCs massively accumulate in human cancers including colorectal cancer, [52][53][54] our findings thus raise the notion that in addition to the tumor cells, the PDL1 C MDSCs might be another major source of PD-L1 that inhibits tumor-infiltrating CTL activation and function in the tumor microenvironment. 17,55 The relative role of these PDL1 C MDSCs in colon cancer immune escape and resistance to immune checkpoint immunotherapy requires further studies.…”

Section: Discussionmentioning

confidence: 66%

The expression profiles and regulation of PD-L1 in tumor-induced myeloid-derived suppressor cells

et al. 2016

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Programmed death-ligand 1 (PD-L1) is an inhibitory ligand that binds to PD-1 to suppress T cell activation. PD-L1 is constitutively expressed and inducible in tumor cells, but the expression profiles and regulatory mechanism of PD-L1 in myeloid-derived suppressor cells (MDSCs) are largely unknown. We report that PD-L1 is abundantly expressed in tumor-infiltrating leukocytes in human patients with both microsatellite instable and microsatellite stable colon cancer. About 60% CD11b PD-L1C MDSCs are also significantly higher in tumor-bearing mice than in tumor-free mice. Interestingly, the highest PD-L1C MDSCs were observed in the tumor microenvironment in which 56-71% tumor-infiltrating MDSCs are PD-L1 C in vivo. In contrast, PD-L1 C MDSCs are significantly less in secondary lymphoid organs and peripheral blood as compared to the tumor tissues, whereas bone marrow MDSCs are essentially PD-L1¡ in tumor-bearing mice. IFNg is highly expressed in cells of the tumor tissues and IFNg neutralization significantly decreased PD-L1 C MDSCs in the tumor microenvironment in vivo. However, IFNg-activated pSTAT1 does not bind to the cd274 promoter in MDSCs. Instead, pSTAT1 activates expression of IRF1, IRF5, IRF7 and IRF8 in MDSCs, and only pSTAT1-activated IRF1 binds to a unique IRF-binding sequence element in vitro and chromatin in vivo in the cd274 promoter to activate PD-L1 transcription. Our data determine that PD-L1 is highly expressed in tumor-infiltrating MDSCs and in a lesser degree in lymphoid organs, and the pSTAT1-IRF1 axis regulates PD-L1 expression in MDSCs.

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Section: Discussionmentioning

confidence: 66%

The expression profiles and regulation of PD-L1 in tumor-induced myeloid-derived suppressor cells

et al. 2016

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“…Previous study found that some monocyte chemokines, such as MCP-1 (monocyte chemotactic protein 1), CCL (CC chemokine ligand) 3, CCL4 and CCL5 contributed to migration of immature myeloid cells [29,30], which were increased in lupus-prone mice [31]. We found that the expression of MCP-1, CCL3, CCL4 and CCL5 was all increased in spleen ( Figure 5A) and PBMCs ( Figure 5B pathogenesis [32], but also were critical for recruitment of neutrophils [33,34] and MDSCs [35]. Expression of CCR1 and CCR5 in splenic G-MDSCs and M-MDSCs was measured.…”

Section: Chemokine Receptor 1 (Ccr1) Contributes To Accumulation Omentioning

confidence: 82%

Myeloid-derived suppressor cells contribute to systemic lupus erythaematosus by regulating differentiation of Th17 cells and Tregs

Zhao

et al. 2016

Clinical Science

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Although major advancements have made in investigating the aetiology of SLE (systemic lupus erythaematosus), the role of MDSCs (myeloid-derived suppressor cells) in SLE progression remains confused. Recently, some studies have revealed that MDSCs play an important role in lupus mice. However, the proportion and function of MDSCs in lupus mice and SLE patients are still poorly understood. In the present study, we investigated the proportion and function of MDSCs using different stages of MRL/lpr lupus mice and specimens from SLE patients with different activity. Results showed that splenic granulocytic (G-)MDSCs were significantly expanded by increasing the expression of CCR1 (CC chemokine receptor 1) in diseased MRL/lpr lupus mice and in high-disease-activity SLE patients. However, the proportion of monocytic (M-)MDSCs remains similar in MRL/lpr lupus mice and SLE patients. G-MDSCs produce high levels of ROS (reactive oxygen species) through increasing gp91(phox) expression, and activated TLR2 (Toll-like receptor 2) and AIM2 (absent in melanoma 2) inflammasome in M-MDSCs lead to IL-1β (interleukin 1β) expression in diseased MRL/lpr mice and high-disease-activity SLE patients. Previous study has revealed that MDSCs could alter the plasticity of Th17 (T helper 17) cells and Tregs (regulatory T-cells) via ROS and IL-1β. Co-culture experiments showed that G-MDSCs impaired Treg differentiation via ROS and M-MDSCs promoted Th17 cell polarization by IL-1β in vitro Furthermore, adoptive transfer or antibody depletion of MDSCs in MRL/lpr mice confirmed that MDSCs influenced the imbalance of Tregs and Th17 cells in vivo Our results indicate that MDSCs with the capacity to regulate Th17 cell/Treg balance may be a critical pathogenic factor in SLE.

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“…HT29, but not Caco2, is a SMAD4-deficient colon cancer cell and loss of SMAD4 correlates with elevated CCL15 expression. 39,40 This is of particular interest, because in a mouse xenograft model, CCL15 secreted from SMAD4-deficient colon cancer cells recruited CCR1 + cells, resulting in aggressive tumor growth and metastasis. In the same study, it was found that CCL15 positively correlated with a worse survival in patients with CRC.…”

Section: Discussionmentioning

confidence: 99%

“…In the same study, it was found that CCL15 positively correlated with a worse survival in patients with CRC. 39,40 Human MC express surface receptors for CCL15, which are CCR1 and CCR3. 19 Therefore, based on our current data it is reasonable to speculate that MC may be among those infiltrating CCR1 + cells and subsequently contribute to colon cancer growth.…”

Section: Discussionmentioning

confidence: 99%

Human mast cells promote colon cancer growth via bidirectional crosstalk: studies in 2D and 3D coculture models

Blokhuis

Derks

et al. 2018

OncoImmunology

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Chronic inflammation drives the development of colorectal cancer (CRC), where tumor-infiltrating immune cells interact with cancer cells in a dynamic crosstalk. Mast cells (MC), one of earliest recruited immune cells, accumulate in CRC tissues and their density is correlated with cancer progression. However, the exact contribution of MC in CRC and their interaction with colon cancer cells is poorly understood. Here, we investigated the impact of primary human MC and their mediators on colon cancer growth using 2D and 3D coculture models. Primary human MC were generated from peripheral CD34+ stem cells. Transwell chambers were used to analyze MC chemotaxis to colon cancer. Colon cancer cells HT29 and Caco2 differentially recruited MC by releasing CCL15 or SCF, respectively. Using BrdU proliferation assays, we demonstrated that MC can directly support colon cancer proliferation and this effect was mediated by their cellular crosstalk. 3D coculture models with cancer spheroids further confirmed the pro-tumor effect of MC on colon cancer growth, where direct cell-cell contact is dispensable and increased production of multiple soluble mediators was detected. Moreover, TLR2 stimulation of MC promoted stronger growth of colon cancer spheroids. By examining the transcriptome profile of colon cancer-cocultured MC versus control MC, we identified several MC marker genes, which were deregulated in expression. Our study provides an advanced in vitro model to investigate the role of human MC in cancer. Our data support the detrimental role of MC in CRC development and provide a molecular insight into the cellular crosstalk between MC and colon cancer cells.

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Loss of SMAD4 Promotes Colorectal Cancer Progression by Accumulation of Myeloid-Derived Suppressor Cells through the CCL15–CCR1 Chemokine Axis

Cited by 108 publications

References 28 publications

The expression profiles and regulation of PD-L1 in tumor-induced myeloid-derived suppressor cells

The expression profiles and regulation of PD-L1 in tumor-induced myeloid-derived suppressor cells

Myeloid-derived suppressor cells contribute to systemic lupus erythaematosus by regulating differentiation of Th17 cells and Tregs

Human mast cells promote colon cancer growth via bidirectional crosstalk: studies in 2D and 3D coculture models

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