Gemcitabine reduces MDSCs, tregs and TGFβ-1 while restoring the teff/treg ratio in patients with pancreatic cancer

Eriksson, Emma; Wenthe, Jessica; Irenaeus, Sandra; Loskog, Angelica; Ullenhag, Gustav

doi:10.1186/s12967-016-1037-z

Cited by 170 publications

(154 citation statements)

References 38 publications

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“…Low dose chemotherapy has been shown to be effective in eliminating MDSC populations in tumour-bearing mice; treatments with chemotherapy such as 5-fluorouracil (5FU), paclitaxel, cisplatin, and gemcitabine were found to deplete MDSCs and enhance anti-tumour immune activity [200][201][202][203]. However, a contrasting effect in the use of chemotherapy against MDSC was observed where MDSCs were transiently induced following cyclophosphamide treatment in tumour-bearing mice and patients [204,205].…”

Section: Depleting Mdsc Populationsmentioning

confidence: 99%

Myeloid-Derived Suppressor Cells as a Therapeutic Target for Cancer

Law

Valdés-Mora

Gallego‐Ortega

2020

Cells

334

272

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The emergence of immunotherapy has been an astounding breakthrough in cancer treatments. In particular, immune checkpoint inhibitors, targeting PD-1 and CTLA-4, have shown remarkable therapeutic outcomes. However, response rates from immunotherapy have been reported to be varied, with some having pronounced success and others with minimal to no clinical benefit. An important aspect associated with this discrepancy in patient response is the immune-suppressive effects elicited by the tumour microenvironment (TME). Immune suppression plays a pivotal role in regulating cancer progression, metastasis, and reducing immunotherapy success. Most notably, myeloid-derived suppressor cells (MDSC), a heterogeneous population of immature myeloid cells, have potent mechanisms to inhibit T-cell and NK-cell activity to promote tumour growth, development of the pre-metastatic niche, and contribute to resistance to immunotherapy. Accumulating research indicates that MDSC can be a therapeutic target to alleviate their pro-tumourigenic functions and immunosuppressive activities to bolster the efficacy of checkpoint inhibitors. In this review, we provide an overview of the general immunotherapeutic approaches and discuss the characterisation, expansion, and activities of MDSCs with the current treatments used to target them either as a single therapeutic target or synergistically in combination with immunotherapy.

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Section: Depleting Mdsc Populationsmentioning

confidence: 99%

Myeloid-Derived Suppressor Cells as a Therapeutic Target for Cancer

Law

Valdés-Mora

Gallego‐Ortega

2020

Cells

334

272

View full text Add to dashboard Cite

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“…It is also possible that vaccines upregulate multiple immune escape mechanisms, and elucidation of these would be necessary to ensure vaccine efficacy. As chemotherapy transiently depletes suppressive Tregs in PDAC patients (37–39), chemotherapy should be considered in addition to administration of an immunomodulatory agent to attempt to overcome the potent immunosuppressive TME.…”

Section: Clinical Challenges In Developing Immunotherapies For Pdacmentioning

confidence: 99%

“…(Table 1). Gemcitabine-based chemotherapy is often used as the chemotherapy backbone in these combination immunotherapy trials because it has been shown to increase tumor antigen availability, and transiently deplete immunosuppressive Tregs and myeloid derived suppressor cells (MDSC) in the PDAC TME (37–39,126). Lower numbers of intratumoral Tregs are associated with increased disease free survival after pancreatectomy (30), suggesting that Treg accumulation is an important determinant of survival in patients with PDAC.…”

Section: Vaccine Immunotherapy Strategies For Pdac Treatmentmentioning

confidence: 99%

“…In phase II studies, gemcitabine based therapy synergizes with IDO inhibition to improve response rates in PDAC (133), possibly via transient depletion of Tregs (39). This provides an immune system reset, allowing for chemotherapy-mediated elimination of previously activated Tregs, followed by indoximod mediated inhibition of subsequent Treg activation.…”

Section: Figurementioning

confidence: 99%

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Strategies for Increasing Pancreatic Tumor Immunogenicity

Johnson

Yarchoan

Lee

et al. 2017

Clinical Cancer Research

140

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Immunotherapy has changed the standard of care for multiple deadly cancers including lung, head and neck, gastric, and some colorectal cancers. However, single agent immunotherapy has had little effect in pancreatic adenocarcinoma (PDAC). Increasing evidence suggests that the PDAC microenvironment is comprised of an intricate network of signals between immune cells, PDAC cells, and stroma, resulting in an immunosuppressive environment resistant to single agent immunotherapies. In this review, we discuss differences between immunotherapy sensitive cancers and PDAC, the complex interactions between PDAC stroma and suppressive tumor infiltrating cells that facilitate PDAC development and progression, the immunologic targets within these complex networks that are drugable, and data supporting combination drug approaches that modulate multiple PDAC signals, which should lead to improved clinical outcomes.

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“…In our intraperitoneal‐dissemination and liver‐metastasis PDAC mice models, GEM treatment decreased numbers of myeloid cells and increased CD4+ and CD8+ cells. In other cancer mice model, GEM was proven to be suppressive to myeloid‐lineage cells, especially, myeloid‐derived suppressor cells . Additionally, in BALB/c mice system, GEM depleted B‐lymphocytes; in contrast, tumor‐specific CD4+ and CD8+ cells were augmented .…”

Section: Discussionmentioning

confidence: 99%

Distinct chemotherapy‐associated anti‐cancer immunity by myeloid cells inhibition in murine pancreatic cancer models

et al. 2019

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Pancreatic ductal adenocarcinoma (PDAC) is a lethal malignancy associated with an extremely poor prognosis. Chemotherapy, such as gemcitabine (GEM), is the only treatment for PDAC patients who are not suitable for radical surgical treatment; however, its anti‐tumor efficacy is limited. In this study, we investigated the host immune system response in murine PDAC models undergoing GEM treatment. We found that PDAC tumor tissues were infiltrated with a substantial number of Gr‐1+ myeloid cells and had relatively small numbers of CD4+ and CD8+ cells. In addition, there were increased numbers of myeloid cells expressing CD11b+ and Gr‐1+ in peripheral blood. When mice with PDAC tumors in the intraperitoneal cavity or liver were treated with GEM, numbers of myeloid cells in tumor tissues and in peripheral blood decreased. In contrast, numbers of CD4+ or CD8+ cells increased. In peripheral blood, the numbers of CD8+ cells expressing interferon‐gamma (IFN‐γ) were higher in GEM‐treated mice than in untreated mice. In addition, GEM treatment in combination with myeloid cell depletion further prolonged the survival of PDAC mice. The gene expression profile of peripheral blood in myeloid cell‐depleted PDAC mice treated with GEM showed biological processes related to anti‐cancer immunity, such as natural killer cell‐mediated cytotoxicity, type I IFN signaling, and co‐stimulatory signaling for T cell activation. Thus, in PDAC murine models, GEM treatment was associated with an immune response consistent with an anti‐cancer effect, and depletion of myeloid‐lineage cells played an important role in enhancing anti‐cancer immunity associated with GEM treatment.

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Gemcitabine reduces MDSCs, tregs and TGFβ-1 while restoring the teff/treg ratio in patients with pancreatic cancer

Cited by 170 publications

References 38 publications

Myeloid-Derived Suppressor Cells as a Therapeutic Target for Cancer

Myeloid-Derived Suppressor Cells as a Therapeutic Target for Cancer

Strategies for Increasing Pancreatic Tumor Immunogenicity

Distinct chemotherapy‐associated anti‐cancer immunity by myeloid cells inhibition in murine pancreatic cancer models

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