Murine Pancreatic Adenocarcinoma Dampens SHIP-1 Expression and Alters MDSC Homeostasis and Function

Pilon‐Thomas, Shari; Nelson, Nadine; Vohra, Nasreen A.; Jerald, Maya; Pendleton, Laura C.; Szekeres, Károly; Ghansah, Tomar

doi:10.1371/journal.pone.0027729

Cited by 45 publications

(55 citation statements)

References 46 publications

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“…In contrast, the level of pSTAT3 in cytokine-treated cells was strongly elevated compared with nontreated cells, whereas the total amount of STAT3 in both cells was nearly the same. These data are in agreement with the previous observation that the reduction of SHIP-1 and PTEN levels results in an increase in STAT3 activity, leading to MDSC expansion (33,34). Next, we sorted MDSC from tumor-bearing mice and compared their PTEN, SHIP-1, pSTAT3, and STAT3 levels with those in peripheral leukocytes from control mice.…”

Section: Mir-155 and Mir-21 Synergistically Enhance Mdsc Expansion VIsupporting

confidence: 91%

MicroRNA-155 and MicroRNA-21 Promote the Expansion of Functional Myeloid-Derived Suppressor Cells

Liu

Zhang

Diao

et al. 2014

The Journal of Immunology

165

162

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Myeloid-derived suppressor cells (MDSC) are one of the main cell populations that negatively regulate immune responses. However, the mechanism underlying the expansion of MDSC remains unclear. Using miRNA microarray and TaqMan probe–based quantitative RT-PCR assay, we identified microRNA (miR)-155 and miR-21 as the two most upregulated miRNAs during the induction of MDSC from the bone marrow cells by GM-CSF and IL-6. High levels of miR-155 and miR-21 also were detected in bone marrow and spleen MDSC isolated from tumor-bearing mice. Our results also showed that TGF-β promoted the induction of MDSC through upregulating miR-155 and miR-21 expression. Overexpression of miR-155 and miR-21 enhanced whereas depletion of miR-155 and miR-21 reduced the frequencies of cytokine-induced MDSC. Subpopulation analysis indicated that miR-21 and miR-155 induced the expansion of both monocytic and granulocytic MDSC. Furthermore, miR-155 and miR-21 showed a synergistic effect on MDSC induction via targeting SHIP-1 and phosphatase and tensin homolog, respectively, leading to STAT3 activation. Finally, dexamethasone treatment strongly enhanced MDSC expansion through upregulating miR-155 and miR-21 expression, and the effect of dexamethasone on MDSC induction was abolished by depleting cellular miR-155 and miR-21. These results demonstrate a novel miR-155/miR-21–based regulatory mechanism that modulates functional MDSC induction.

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Section: Mir-155 and Mir-21 Synergistically Enhance Mdsc Expansion VIsupporting

confidence: 91%

MicroRNA-155 and MicroRNA-21 Promote the Expansion of Functional Myeloid-Derived Suppressor Cells

Liu

Zhang

Diao

et al. 2014

The Journal of Immunology

165

162

View full text Add to dashboard Cite

show abstract

“…Regulatory T cells (Tregs) or myeloid derived suppressors cells (MDSC) are also known to blunt T cell responses (12,13). Tregs suppress antigen-specific T cell response and removal of Tregs in murine models led to enhanced anti-tumor T cell responses and tumor rejection (14).…”

Section: Introductionmentioning

confidence: 99%

Neutralization of Tumor Acidity Improves Antitumor Responses to Immunotherapy

et al. 2016

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Cancer immunotherapies, such as immune checkpoint blockade or adoptive T cell transfer, can lead to durable responses in the clinic, but response rates remain low due to undefined suppression mechanisms. Solid tumors are characterized by a highly acidic microenvironment that might blunt the effectiveness of anti-tumor immunity. In this study, we directly investigated the effects of tumor acidity on the efficacy immunotherapy. An acidic pH environment blocked T cell activation and limited glycolysis in vitro. IFNγ release blocked by acidic pH did not occur at the level of steady-state mRNA, implying that the effect of acidity was post-translational. Acidification did not affect cytoplasmic pH, such that signals transduced by external acidity were like mediated by specific acid-sensing receptors, four of which are expressed by T cells. Notably, neutralizing tumor acidity with bicarbonate monotherapy impaired the growth of some cancer types in mice where it was associated with increased T cell infiltration. Further, combining bicarbonate therapy with anti-CTLA-4, anti-PD1 or adoptive T cell transfer improved antitumor responses in multiple models, including cures in some subjects. Overall, our findings show how raising intratumoral pH through oral buffers therapy can improve responses to immunotherapy, with the potential for immediate clinical translation.

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“…79 In addition, SHIP-1-regulated MDSC expansion and function may contribute to pancreatic tumor progression. 80 …”

Section: Src Homology 2 Domain-containing Inositol 59-phosphatase-1mentioning

confidence: 99%

Phenotype, development, and biological function of myeloid-derived suppressor cells

et al. 2015

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Murine Pancreatic Adenocarcinoma Dampens SHIP-1 Expression and Alters MDSC Homeostasis and Function

Cited by 45 publications

References 46 publications

MicroRNA-155 and MicroRNA-21 Promote the Expansion of Functional Myeloid-Derived Suppressor Cells

MicroRNA-155 and MicroRNA-21 Promote the Expansion of Functional Myeloid-Derived Suppressor Cells

Neutralization of Tumor Acidity Improves Antitumor Responses to Immunotherapy

Phenotype, development, and biological function of myeloid-derived suppressor cells

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