Immunosuppression by monocytic myeloid-derived suppressor cells in patients with pancreatic ductal carcinoma is orchestrated by STAT3

Trovato, Rosalinda; Fiore, Alessandra; Sartori, S; Canè, Stefania; Giugno, Rosalba; Cascione, Luciano; Paiella, Salvatore; Salvia, Roberto; Sanctis, Francesco De; Poffe, Ornella; Anselmi, Cristina; Hofer, Francesca; Sartoris, Silvia; Piro, Geny; Carbone, Carmine; Corbo, Vincenzo; Lawlor, Rita T.; Solito, Samantha; Pinton, Laura; Mandruzzato, Susanna; Bassi, Claudio; Scarpa, Aldo; Bronte, Vincenzo; Ugel, Stefano

doi:10.1186/s40425-019-0734-6

Cited by 144 publications

(158 citation statements)

References 59 publications

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“…In general, M-MDSCs are more immunosuppressive than PMN-MDSCs on a per cell basis both in tumor-bearing mice (15,38) and cancer patients (31). Moreover, M-MDSCs exhibit longer half-life and more pronounced cell plasticity compared to PMN-MDSCs since they are able to differentiate into tumor-associated macrophages (TAMs) (39), as well as they can act as "precursors" to maintain circulating PMN-MDSCs level (38).…”

Section: Mdsc: a Tumor-induced Myeloid Cell Subsetmentioning

confidence: 99%

“…The MDSC plasticity and functions are strictly guided by the activation of precise signaling pathways [extensively reviewed in (8,45)] preferentially driven by c/EBPβ (CCAAT/enhancerbinding protein) (16), STAT3 (signal transducer and activator of transcription 3) (31,46) and NF-κB (42,47) transcriptional factors. c/EBPβ is the master regulator of "emergency" myelopoiesis and its critical role on MDSC biology was proved using myeloid-restricted c/EBPβ-deficient mice engrafted with different tumor models in which the ontogeny and MDSCassociated immunosuppression were completely abrogated (16).…”

Section: Mdsc: a Tumor-induced Myeloid Cell Subsetmentioning

confidence: 99%

“…In particular activated STAT3 triggers on one hand the production of pro-inflammatory proteins, like S100A8/A9 (54) that interfere with DC differentiation and sustain ROS generation (55); on the other hand by binding to the arginase 1 (ARG1) promoter, STAT3 favors its aberrant expression (46). Interestingly, we recently demonstrated a unique STAT3-dependent expression of ARG1 in a subset of cancer patient-derived monocytes (31). NF-κB, the master regulator of inflammation, was reported to be involved in MDSC differentiation.…”

Section: Mdsc: a Tumor-induced Myeloid Cell Subsetmentioning

confidence: 99%

“…The pro-tumor role of ARG1 was partially confirmed by clinical evidences. Indeed, the frequency of ARG1-expressing MDSCs significantly discriminate PDAC metastatic patients suggesting that these cells have a pro-metastatic potential (31), as well as the reduction of ARG1 + cells in melanoma patients after Ipilimumab-based treatment highlights that the therapeutic efficacy of this immune-based treatment might involve a systemic effect on MDSC accumulation (84). Indeed, a contraction of MDSCs in a Durvalumab responder patient was also reported in lung adenocarcinoma setting (85), suggesting that MDSC enumeration might be a useful biomarker to stratify immunotherapy-undergoing patients.…”

Section: Mdscs Promote Primary Tumor Growth and Local Invasionmentioning

confidence: 99%

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The Engagement Between MDSCs and Metastases: Partners in Crime

et al. 2020

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Tumor metastases represent the major cause of cancer-related mortality, confirming the urgent need to identify key molecular pathways and cell-associated networks during the early phases of the metastatic process to develop new strategies to either prevent or control distal cancer spread. Several data revealed the ability of cancer cells to establish a favorable microenvironment, before their arrival in distant organs, by manipulating the cell composition and function of the new host tissue where cancer cells can survive and outgrow. This predetermined environment is termed "pre-metastatic niche" (pMN). pMN development requires that tumor-derived soluble factors, like cytokines, growth-factors and extracellular vesicles, genetically and epigenetically reprogram not only resident cells (i.e., fibroblasts) but also non-resident cells such as bone marrow-derived cells. Indeed, by promoting an "emergency" myelopoiesis, cancer cells switch the steady state production of blood cells toward the generation of pro-tumor circulating myeloid cells defined as myeloid-derived suppressor cells (MDSCs) able to sustain tumor growth and dissemination. MDSCs are a heterogeneous subset of myeloid cells with immunosuppressive properties that sustain metastatic process. In this review, we discuss current understandings of how MDSCs shape and promote metastatic dissemination acting in each fundamental steps of cancer progression from primary tumor to metastatic disease.

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Section: Mdsc: a Tumor-induced Myeloid Cell Subsetmentioning

confidence: 99%

Section: Mdsc: a Tumor-induced Myeloid Cell Subsetmentioning

confidence: 99%

Section: Mdsc: a Tumor-induced Myeloid Cell Subsetmentioning

confidence: 99%

Section: Mdscs Promote Primary Tumor Growth and Local Invasionmentioning

confidence: 99%

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The Engagement Between MDSCs and Metastases: Partners in Crime

et al. 2020

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“…Negative m-melanoma CD11b+ [28] Cxcl2, Cxcl12 positive m-melanoma BMDM+Tumor conditioned media [31] MDSC: CD11b+ GR1+ CD11c− [22] Scavenger receptors/Endocytosis Mrc1 (CD206) positive m-breast CD11b+ Ly-6C lo F4/80 hi CD24 lo MHC-II lo [32] CD163 positive h-gastric CD163+ CD209a+ [33] h-SCC ERK5+ CD163+ [23] m-PDAC CD68+, IL-10Ra+ [29] Cd209a positive m-PDAC CD68+, IL-10Ra+ [29] Immune suppression Arg1 positive m-PDAC; h-PDAC CD68+, IL-10Ra+ [29]; blood CD14+ [34] Cox2 positive m-melanoma BMDM + Tumor conditioned media [31] Ido1 positive m-liver metastasis liver-MDSC: CD11b+ Ly-6C int/hi Ly-6G + [35] Pdl1 (CD274) positive h-& m-glioma h-CD68+; m-CD11b+ CD115+ [36] h-breast CD163+ [37] m-liver metastasis liver-MDSC: CD11b+ Ly-6C int/hi Ly-6G + [35] Extra-cellular Matrix/Angiogenesis Mmp2 positive m-melanoma BMDM + Tumor conditioned media [31] Vegf positive m-melanoma CD11b+ [28]; MDSC: CD11b+ GR1+ CD11c- [22] Cathepsin (B, L) positive m-PDAC CD68+, IL-10Ra+ [29] Cell cycle/TFs Ccnd1 positive m-melanoma BMDM + Tumor conditioned media [31] ATF6, sXBP1 positive m-PDAC CD68+, IL-10Ra+ [29] * Immune suppressive cytokines.…”

Section: Introductionmentioning

confidence: 99%

Targeting STAT3 and STAT5 in Tumor-Associated Immune Cells to Improve Immunotherapy

Verdeil

Lawrence

Schmitt-Verhulst

et al. 2019

Cancers

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Oncogene-induced STAT3-activation is central to tumor progression by promoting cancer cell expression of pro-angiogenic and immunosuppressive factors. STAT3 is also activated in infiltrating immune cells including tumor-associated macrophages (TAM) amplifying immune suppression. Consequently, STAT3 is considered as a target for cancer therapy. However, its interplay with other STAT-family members or transcription factors such as NF-κB has to be considered in light of their concerted regulation of immune-related genes. Here, we discuss new attempts at re-educating immune suppressive tumor-associated macrophages towards a CD8 T cell supporting profile, with an emphasis on the role of STAT transcription factors on TAM functional programs. Recent clinical trials using JAK/STAT inhibitors highlighted the negative effects of these molecules on the maintenance and function of effector/memory T cells. Concerted regulation of STAT3 and STAT5 activation in CD8 T effector and memory cells has been shown to impact their tumor-specific responses including intra-tumor accumulation, long-term survival, cytotoxic activity and resistance toward tumor-derived immune suppression. Interestingly, as an escape mechanism, melanoma cells were reported to impede STAT5 nuclear translocation in both CD8 T cells and NK cells. Ours and others results will be discussed in the perspective of new developments in engineered T cell-based adoptive therapies to treat cancer patients. function of tumor-associated macrophages (TAM) and (ii) for the regulation of T cell functions. As STAT TFs are key players in the regulation of functions of these immune cells, their manipulation can have a beneficial or detrimental effect on the anti-tumor response depending on the targeted cell type. Tumor-Induced Inflammation Drives Accumulation of Tumor-Infiltrating Myeloid CellsCytokine receptor-induced signaling sustains and amplifies the activation of STAT3, NF-κB and AP-1 in a positive amplification loop, fueling tumor-associated inflammation. As such, a core inflammation-related gene set regulated by STAT3, NF-κB and AP-1 has recently been proposed as an "inflammatory index" in breast cancer cell lines and patient samples [4]. Importantly, in correlation with this inflammatory index, this study reported a concerted regulation of (i) non-inflammatory genes related to angiogenesis, metastasis, and cell proliferation; (ii) tumor genome instability; and (iii) heterogeneity of the tumor microenvironment (TME), including the recruited immune cells. Remarkably, these co-regulated characteristics were found across several cancer types driven by distinct oncogenes [4].Tumor-derived cytokines have been linked to the accumulation of immune-suppressive myeloid cells including both myeloid-derived suppressor cells (MDSCs; IMCs) and tumor-associated macrophages (TAM). In both human and mouse melanomas, IMCs have an important role in malignant progression and evasion from anti-tumor immunity that is linked to the suppression of T cell responses [6][7][8][9]. While increased...

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Microglia and macrophages in glioblastoma: landscapes and treatment directions

Solomou,

Young,

Bulstrode

2024

Molecular Oncology

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Glioblastoma is the most common primary malignant tumour of the central nervous system and remains uniformly and rapidly fatal. The tumour‐associated macrophage (TAM) compartment comprises brain‐resident microglia and bone marrow‐derived macrophages (BMDMs) recruited from the periphery. Immune‐suppressive and tumour‐supportive TAM cell states predominate in glioblastoma, and immunotherapies, which have achieved striking success in other solid tumours have consistently failed to improve survival in this ‘immune‐cold’ niche context. Hypoxic and necrotic regions in the tumour core are found to enrich, especially in anti‐inflammatory and immune‐suppressive TAM cell states. Microglia predominate at the invasive tumour margin and express pro‐inflammatory and interferon TAM cell signatures. Depletion of TAMs, or repolarisation towards a pro‐inflammatory state, are appealing therapeutic strategies and will depend on effective understanding and classification of TAM cell ontogeny and state based on new single‐cell and spatial multi‐omic in situ profiling. Here, we explore the application of these datasets to expand and refine TAM characterisation, to inform improved modelling approaches, and ultimately underpin the effective manipulation of function.

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Immunosuppression by monocytic myeloid-derived suppressor cells in patients with pancreatic ductal carcinoma is orchestrated by STAT3

Cited by 144 publications

References 59 publications

The Engagement Between MDSCs and Metastases: Partners in Crime

The Engagement Between MDSCs and Metastases: Partners in Crime

Targeting STAT3 and STAT5 in Tumor-Associated Immune Cells to Improve Immunotherapy

Microglia and macrophages in glioblastoma: landscapes and treatment directions

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