Immunosuppressive and Prometastatic Functions of Myeloid-Derived Suppressive Cells Rely upon Education from Tumor-Associated B Cells

Bodogai, Monica; Moritoh, Kanako; Lee-Chang, Catalina; Hollander, Christine M.; Sherman-Baust, Cheryl A.; Wersto, Robert P.; Araki, Yoshihiko; Miyoshi, Isao; Yang, Li; Trinchieri, Giorgio; Biragyn, Arya

doi:10.1158/0008-5472.can-14-3077

Cited by 129 publications

(113 citation statements)

References 41 publications

(77 reference statements)

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“…While B cells reportedly support MDSC development during cancer progression (Bodogai et al, 2015), to our knowledge this is the first demonstration that B cells are targets of tumor-induced MDSC. These findings complement studies in autoimmunity showing that MDSC derived from mice with collagen-induced arthritis directly suppress B cell proliferation and antibody production in vitro (Crook et al, 2015).…”

Section: Discussionmentioning

confidence: 78%

Tumor-induced MDSC act via remote control to inhibit L-selectin-dependent adaptive immunity in lymph nodes

Muhitch

Powers

et al. 2016

eLife

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Myeloid-derived suppressor cells (MDSC) contribute to an immunosuppressive network that drives cancer escape by disabling T cell adaptive immunity. The prevailing view is that MDSC-mediated immunosuppression is restricted to tissues where MDSC co-mingle with T cells. Here we show that splenic or, unexpectedly, blood-borne MDSC execute far-reaching immune suppression by reducing expression of the L-selectin lymph node (LN) homing receptor on naïve T and B cells. MDSC-induced L-selectin loss occurs through a contact-dependent, post-transcriptional mechanism that is independent of the major L-selectin sheddase, ADAM17, but results in significant elevation of circulating L-selectin in tumor-bearing mice. Even moderate deficits in L-selectin expression disrupt T cell trafficking to distant LN. Furthermore, T cells preconditioned by MDSC have diminished responses to subsequent antigen exposure, which in conjunction with reduced trafficking, severely restricts antigen-driven expansion in widely-dispersed LN. These results establish novel mechanisms for MDSC-mediated immunosuppression that have unanticipated implications for systemic cancer immunity.DOI: http://dx.doi.org/10.7554/eLife.17375.001

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Section: Discussionmentioning

confidence: 78%

Tumor-induced MDSC act via remote control to inhibit L-selectin-dependent adaptive immunity in lymph nodes

Muhitch

Powers

et al. 2016

eLife

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“…Transforming growth factor β (TGFβ), G-CSF and interferon β (IFNβ) are the most well-studied molecules in this process. TGFβ and G-CSF activate a tumor-and metastasispromoting program 25,27,65,[85][86][87][88] , by regulating the transcription factors inhibitor of DNA 1 (ID1), retinoblastoma 1 (RB1) and interferon regulatory factor 8 (IRF8) that control the immunosuppressive functions of neutrophils 25,87,89,90 . IFNβ acts as a negative regulator of the pro-tumorigenic phenotype of neutrophils 91,92 .…”

Section: Tumor-induced Neutrophil Polarization and Activationmentioning

confidence: 99%

Neutrophils in cancer: neutral no more

2016

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SummaryNeutrophils are indispensable antagonists of microbial infection and facilitators of wound healing. In the cancer setting, a newfound appreciation for neutrophils has come into view.The traditionally held belief that neutrophils are inert bystanders is being challenged by recent literature. Emerging evidence indicates that tumors manipulate neutrophils, sometimes early in their differentiation process, to create diverse phenotypic and functional polarization states able to alter tumor behavior. In this Review, we discuss the involvement of neutrophils in cancer initiation and progression, and their potential as clinical biomarkers and therapeutic targets. 2The name neutrophil -given to polymorphonuclear, granulocytic cells by Paul Ehrlich in the late 19th century -is based on the inability of these cells to retain acidic or basic dyes and for their preferential uptake of pH neutral dyes 1 . Although their neutral staining led to the identification of these cells, neutrophils in the cancer setting are anything but neutral.Neutrophils in tumor-bearing hosts can oppose or potentiate cancer progression. These two types of behavior are controlled by signals emanating from cancer cells or stromal cells within the tumor microenvironment, which educate neutrophils to execute the demise of the tumor or facilitate support networks that lead to its expansive spread. These functions can occur locally in or around the tumor microenvironment, as well as systemically in distant organs.Until the past few years, other immune cells such as macrophages have overshadowed the role of neutrophils in cancer. But recent studies and the development of new genetic tools have provided the cancer community with new insights into the profound influence of these dynamic cells by uncovering distinct capabilities for neutrophils throughout each step of carcinogenesis: from tumor initiation to primary tumor growth to metastasis.During these processes, neutrophils take on different phenotypes and sometimes opposing functions. Emerging evidence also indicates that these cells are highly influential, and are able to change the behavior of other tumor-associated cell types -primarily other immune cells. In this Review, we focus on how tumors manipulate the generation and release of neutrophils from the bone marrow. We discuss the mechanisms identified in animal models by which neutrophils participate in tumor initiation, growth and metastasis. Finally, we highlight the potential of these cells as clinical biomarkers and therapeutic targets. In humans, neutrophils are the most abundant immune cell population, representing 50-70% of all leukocytes. Over 10 11 neutrophils may be produced per day 2 , and tumors can increase this number by even more. Indeed, patients with various cancer types, including but not limited to breast, lung and colorectal cancer, often exhibit increased numbers of circulating neutrophils 3,4 . Recent studies have identified key pathways that tumors exploit to disrupt normal neutrophil homeostasis and these are discuss...

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“…Bregs can be generated from the actions of the metabolites of 5-lipoxygenase (such as leukotriene B4), produced by the tumor that activate PPARα in B cells and initiate their differentiation into Bregs [60]. TGFβ produced by Bregs can convert naïve CD4+ T cells into Foxp3+ Tregs, which inhibit NK cells and effector CD8+ CTLs, which would otherwise thwart the metastasis of neoplastic cells [56,57,61]; this finding may explain studies in B cell-deficient μ MT mice implicating B cells in the inhibition of the induction of CTL-mediated tumor immunity by disabling CD4 T cell help [59]. As these tumor-evoked Bregs trigger a chain of events culminating in immune suppression, it is likely that they are continually induced as long as the cancer cells persist [62], thus underscoring the value of finding ways to control and deplete these cells in the course of therapeutic intervention.…”

Section: B Cell Suppression Of the Antitumor Responsementioning

confidence: 99%

“…Tumor Bregs produce TGFβ, which acts on the monocyte and granulocyte subpopulations of MDSCs to upregulate ROS and NO production, both of which are required for the complete and efficient suppression of anti-tumor CD4+ and CD8+ T cells [57]. B cells can also blunt the immunogenic effects of low-dose oxaliplatin, a chemotherapeutic that promotes cell death and CD8+ CTL killing: in one study, three different mouse prostate cancer models showed no response to oxaliplatin unless B cells were depleted [74].…”

Section: B Cell Suppression Of the Antitumor Responsementioning

confidence: 99%