Macrophage Migration Inhibitory Factor Promotes Tumor Growth and Metastasis by Inducing Myeloid-Derived Suppressor Cells in the Tumor Microenvironment

Simpson, Kendra; Templeton, Dennis J.; Cross, Janet V.

doi:10.4049/jimmunol.1201161

Cited by 182 publications

(194 citation statements)

References 48 publications

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“…T-cell suppression (34,50). However, molecules, such as EpsteinBarr virus induced gene 3 (Ebi3, which encodes IL27b) and interleukin-12a (which encodes IL12a/p35), were shown to modulate Treg function (51).…”

Section: Discussionmentioning

confidence: 99%

Tetraspanin CD81 Promotes Tumor Growth and Metastasis by Modulating the Functions of T Regulatory and Myeloid-Derived Suppressor Cells

et al. 2015

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Tumor cells counteract innate and adaptive antitumor immune responses by recruiting regulatory T cells (Treg) and innate myeloid-derived suppressor cells (MDSC), which facilitate immune escape and metastatic dissemination. Here we report a role in these recruitment processes for CD81, a member of the tetraspanin family of proteins that have been implicated previously in cancer progression. We found that genetic deficiency in CD81 reduced tumor growth and metastasis in two genetic mouse backgrounds and multiple tumor models. Mechanistic investigations revealed that CD81 was not required for normal development of Treg and MDSC but was essential for immunosuppressive functions. Notably, adoptive transfer of wild-type Treg into CD81-deficient mice was sufficient to promote tumor growth and metastasis. Our findings suggested that CD81 modulates adaptive and innate immune responses, warranting further investigation of CD81 in immunomodulation in cancer and its progression. Cancer Res; 75(21); 4517-26. Ó2015 AACR.

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Section: Discussionmentioning

confidence: 99%

Tetraspanin CD81 Promotes Tumor Growth and Metastasis by Modulating the Functions of T Regulatory and Myeloid-Derived Suppressor Cells

et al. 2015

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“…PSMP shows no homology to any known chemokines, including CCL2 and CCL8. Recently, several proteins were found to exhibit chemotactic ability without containing the classical CC, CXC, CX3C, or XC characteristic structures, but were similar to classical chemokines in their threedimensional spatial structures and could bind to chemokine receptors; these proteins included MIF (22), b-defensins (10), and a tyrosyl-tRNA-synthetase fragment (11). In one recent study, the threading technique was applied to predict the structural characteristics and function of an unknown protein.…”

Section: Discussionmentioning

confidence: 99%

PC3-Secreted Microprotein Is a Novel Chemoattractant Protein and Functions as a High-Affinity Ligand for CC Chemokine Receptor 2

Pei

Sun

Zhang

et al. 2014

The Journal of Immunology

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PC3-secreted microprotein (PSMP) or microseminoprotein is a newly discovered secreted protein whose function is currently unknown. In this study, PSMP was found to possess chemotactic ability toward monocytes and lymphocytes, and its functional receptor was identified as CCR2B. PSMP was identified as a chemoattractant protein from a PBMC chemoattractant platform screen that we established. The mature secreted PSMP was able to chemoattract human peripheral blood monocytes, PBLs, and CCR2B-expressing THP-1 cells, but not peripheral blood neutrophils, even though it does not contain the classical structure of chemokines. CCR2B was identified as one receptor for PSMP-mediated chemotaxis by screening HEK293 cells that transiently expressed classical chemokine receptors; results obtained from the chemotaxis, calcium flux, receptor internalization, and radioligand-binding assays all confirmed this finding. To further identify the major function of PSMP, we analyzed its expression profile in tissues. PSMP is highly expressed in benign prostatic hyperplasia and in some prostate cancers, and can also be detected in breast tumor tissue. In response to PSMP stimulation, phosphorylated ERK levels downstream of CCR2B signaling were upregulated in the PC3 cell line. Taken together, our data collectively suggest that PSMP is a chemoattractant protein acting as a novel CCR2 ligand that may influence inflammation and cancer development.

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“…Whether accessory cells involved in breast cancer metastasis, such as macrophages (23), MDSC (24)(25)(26), and T cells (27,28) (Fig. 2C).…”

Section: T1 Cells Formed Significantly Lower Numbers Of Metastases Imentioning

confidence: 99%

Osteopontin Shapes Immunosuppression in the Metastatic Niche

et al. 2014

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The matricellular protein osteopontin (OPN, Spp-1) is widely associated with cancer aggressiveness when produced by tumor cells, but its impact is uncertain when produced by leukocytes in the context of the tumor stroma. In a broad study using Spp1 À/À mice along with gene silencing in tumor cells, we obtained evidence of distinct and common activities of OPN when produced by tumor or host cells in a spontaneously metastatic model of breast cancer. Different cellular localization of OPN is associated with its distinct activities, being mainly secreted in tumor cells while intracellular in myeloid cells. OPN produced by tumor cells supported their survival in the blood stream, whereas both tumor-and host-derived OPN, particularly from myeloid cells, rendered the metastatic site more immunosuppressive. Myeloid-derived suppressor cells (MDSC) expanded with tumor progression at both primary and lung metastatic sites. Of the expanded monocytic and granulocytic cell populations of MDSCs, the monocytic subset was the predominant source of OPN. In Spp1 À/À mice, the inhibition of lung metastases correlated with the expansion of granulocyte-oriented MDSCs. Notably, monocytic MDSCs in Spp1 À/À mice were less suppressive than their wild-type counterparts due to lower expression of arginase-1, IL6, and phospho-Stat3. Moreover, fewer regulatory T cells accumulated at the metastatic site in Spp1 À/À mice. Our data find correlation with lung metastases of human mammary carcinomas that are associated with myeloid cells expressing OPN. Overall, our results unveiled novel functions for OPN in shaping local immunosuppression in the lung metastatic niche.

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Macrophage Migration Inhibitory Factor Promotes Tumor Growth and Metastasis by Inducing Myeloid-Derived Suppressor Cells in the Tumor Microenvironment

Cited by 182 publications

References 48 publications

Tetraspanin CD81 Promotes Tumor Growth and Metastasis by Modulating the Functions of T Regulatory and Myeloid-Derived Suppressor Cells

Tetraspanin CD81 Promotes Tumor Growth and Metastasis by Modulating the Functions of T Regulatory and Myeloid-Derived Suppressor Cells

PC3-Secreted Microprotein Is a Novel Chemoattractant Protein and Functions as a High-Affinity Ligand for CC Chemokine Receptor 2

Osteopontin Shapes Immunosuppression in the Metastatic Niche

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