CD45 Phosphatase Inhibits STAT3 Transcription Factor Activity in Myeloid Cells and Promotes Tumor-Associated Macrophage Differentiation

Kumar, Vinit; Cheng, Pingyan; Condamine, Thomas; Mony, Sridevi; Languino, Lucia R.; McCaffrey, Judith C.; Hockstein, Neil; Guarino, Michael J.; Masters, Gregory A.; Penman, Emily; Denstman, Fred; Xu, Xiaowei; Altieri, Dario C.; Du, Hong; Yan, Cong; Gabrilovich, Dmitry I.

doi:10.1016/j.immuni.2016.01.014

Cited by 306 publications

(260 citation statements)

References 40 publications

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“…22 In addition, hypoxia selectively reduces STAT3 activity in MDSC, thus, favoring differentiation to TAM. 32 In the present study, we observed that TLR7 activation directs the differentiation of MDSC toward a mature APC phenotype and decreases MDSC-mediated T-cell suppression, indicating that differentiation into TAM is prevented. Furthermore, we show that TLR7 stimulation of MDSC abolishes their tumor-promoting effect.…”

Section: E1230578-4supporting

confidence: 57%

TLR7-based cancer immunotherapy decreases intratumoral myeloid-derived suppressor cells and blocks their immunosuppressive function

et al. 2016

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Myeloid-derived suppressor cells (MDSC) are a heterogeneous population of immature myeloid cells with the capacity to inhibit immunological responses. During cancer progression, MDSC are recruited to the tumor sites and secondary lymphoid organs, leading to the suppression of the antitumor function of NK and T cells. Here, we show that the TLR7/8 agonist resiquimod (R848) has a direct effect on MDSC populations in tumor-bearing mice. Systemic application of R848 led to a rapid reduction in both intratumoral and circulating MDSC. The subpopulation of monocytic MDSC (m-MDSC) was the most affected by R848 treatment with an up to 5-fold decrease in the tumor. We found that TLR7 stimulation in tumor-bearing mice led to a maturation and differentiation of MDSC with upregulation of the surface molecules CD11c, F4/80, MHC-I, and MHC-II. MDSC treated with R848 lost their immunosuppressive function and acquired instead an antigen-presenting phenotype with the capability to induce specific Tcell proliferation. Importantly, we found that MDSC co-injected s.c. with CT26 tumor cells lost their ability to support tumor growth after pretreatment with R848. Our results demonstrate that treatment of tumorbearing mice with a TLR7/8 agonist acts directly on MDSC to induce their maturation and leads them to acquire a non-suppressive status. Considering the obstacles posed by MDSC for cancer immunotherapy, targeting these cells by a TLR7/8 agonist may improve immune responses against cancer.

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Section: E1230578-4supporting

confidence: 57%

TLR7-based cancer immunotherapy decreases intratumoral myeloid-derived suppressor cells and blocks their immunosuppressive function

et al. 2016

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“…Myeloid-derived suppressor cells (MDSCs) are immature myeloid cells present in tumor-bearing hosts and can be subdivided into monocytic MDSCs (M-MDSCs) and granulocytic MDSCs (G-MDSCs) (58). Within tumors, M-MDSCs, but not GMDSCs, rapidly differentiate into TAMs (14,45,46). Therefore, TAMs may originate from monocytes, by local proliferation, and from M-MDSCs.…”

Section: Macrophage Phenotype In Crcmentioning

confidence: 99%

Colonic macrophage polarization in homeostasis, inflammation, and cancer

Isidro

Appleyard

2016

American Journal of Physiology-Gastrointestinal and Liver Physi

177

150

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Our review focuses on the colonic macrophage, a monocyte-derived, tissue-resident macrophage, and the role it plays in health and disease, specifically in inflammatory conditions such as inflammatory bowel disease and cancer of the colon and rectum. We give special emphasis to macrophage polarization, or phenotype, in these different states. We focus on macrophages because they are one of the most numerous leukocytes in the colon, and because they normally contribute to homeostasis through an anti-inflammatory phenotype. However, in conditions such as inflammatory bowel disease, proinflammatory macrophages are increased in the colon and have been linked to disease severity and progression. In colorectal cancer, tumor cells may employ anti-inflammatory macrophages to promote tumor growth and dissemination, whereas proinflammatory macrophages may antagonize tumor growth. Given the key roles that this cell type plays in homeostasis, inflammation, and cancer, the colonic macrophage is an intriguing therapeutic target. As such, potential macrophage-targeting strategies are discussed.

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“…25 Functionally, MDSC are characterized by increased arginase activity, PD-L1 expression, NADPH-oxidase and inducible nitric oxide synthase activity (iNOS/Nos2) along with an increased production of reactive oxygen/nitrogen species (ROS/RNS), [25][26][27] all of which have been shown to contribute to their ability to suppress T cells. 20 The development of functional MDSC has been shown to require the activity of several transcription factors, including C/EBPb, 27,28 signal transducer, and activator of transcription (STAT) 20,[29][30][31][32] as well as hypoxiainducible factor 1-a (HIF1-a). 20,33 Importantly, numerous studies in mice have shown that the depletion of MDSC or interference with their immunosuppressive activity improves antitumor response and delays tumor growth.…”

Section: Ly6cmentioning

confidence: 99%

“…MDSC differentiation and suppressive function have been shown to be dependent on C/EBPb 27,28 , HIF1-a, 33,57 and STAT [29][30][31][32] transcription factors. Indeed, cells deficient for either of these genes lack suppressive activity.…”

Section: Dznep Alters Expression Of Mdsc Master Regulatorsmentioning

confidence: 99%

Identification of inhibitors of myeloid-derived suppressor cells activity through phenotypic chemical screening

et al. 2016

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Tumors are infiltrated by cells of the immune system that interact through complex regulatory networks. Although tumor-specific CD8 C T cells can be found in peripheral blood and tumor samples from cancer patients, their function is inhibited by immunosuppressive cells such as regulatory T cells, tumorassociated macrophages, and myeloid-derived suppressor cells (MDSC). Recent clinical successes have demonstrated that alleviating immunosuppression and T cell exhaustion translates into long-term clinical benefits. Although tremendous progress has been achieved, tools that afford unbiased approaches and screenings to uncover new potential inhibitors or gene targets are lacking. In this study, we describe a system based on immortalized progenitors that allows straightforward investigation of myeloid cells. We show that bone marrow progenitors immortalized through the transduction of NUP98-HOXB4 transgene can be differentiated into CD11b C Gr-1 C MDSC that express Arginase-1 and PD-L1, produce reactive oxygen and nitrogen species, and suppress T cell function in vitro. To uncover chemical probes that interfere with MDSC biology, we performed a chemical phenotypic screening and identified 3-deazaneplanocin A as a novel modulator of MDSC functions. We characterized and compared the effect of 3-deazaneplanocin-A and all-trans retinoic acid, a well-known modulator of MDSC activity, on the expression of effector molecules and immunosuppressive functions of MDSC. Altogether, this proof-ofprinciple opens new possibilities for the identification of drugs targeting myeloid cells with immunosuppressive activities.

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CD45 Phosphatase Inhibits STAT3 Transcription Factor Activity in Myeloid Cells and Promotes Tumor-Associated Macrophage Differentiation

Cited by 306 publications

References 40 publications

TLR7-based cancer immunotherapy decreases intratumoral myeloid-derived suppressor cells and blocks their immunosuppressive function

TLR7-based cancer immunotherapy decreases intratumoral myeloid-derived suppressor cells and blocks their immunosuppressive function

Colonic macrophage polarization in homeostasis, inflammation, and cancer

Identification of inhibitors of myeloid-derived suppressor cells activity through phenotypic chemical screening

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