Immature myeloid cells directly contribute to skin tumor development by recruiting IL-17–producing CD4+ T cells

Ortiz, Myrna L.; Kumar, Vinit; Martner, Anna; Mony, Sridevi; Donthireddy, Laxminarasimha; Condamine, Thomas; Seykora, John T.; Knight, Stella C.; Malietzis, George; Lee, Gui Han; Moorghen, Morgan; Lenox, Brianna; Luetteke, Noreen; Celis, Esteban; Gabrilovich, Dmitry I.

doi:10.1084/jem.20140835

Cited by 66 publications

(54 citation statements)

References 60 publications

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“…Furthermore, in the context of intestinal chronic inflammation, by inhibiting Th1 responses and producing high levels of IL-1β, IL-6 (not shown) and IL-23 (Fig.4C), MDSCs in the ETBF TME may contribute to the recruitment of Th17 and amplify IL-17-driven ETBF oncogenesis, while, simultaneously, contributing to the promotion of tumors by enabling an environment permissive for tumor growth and angiogenesis (23) . This agrees with recent findings that IMCs are capable of promoting carcinogenesis via mechanisms other than T cell inhibition (33) . Further, it supports our observation that ETBF-associated MO-MDSCs were immunosuppressive in vitro even though they did so at fairly modest levels (approximately 40% inhibition of proliferation) compared to suppression levels of 80-90% typically reported for MDSCs (34) .…”

Section: Discussionsupporting

confidence: 93%

The myeloid immune signature of enterotoxigenic Bacteroides fragilis-induced murine colon tumorigenesis

et al. 2017

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Enterotoxigenic Bacteroides fragilis (ETBF), a human commensal and candidate pathogen in colorectal cancer (CRC), is a potent initiator of IL-17-dependent colon tumorigenesis in MinApc+/-mice. We examined the role of IL-17 and ETBF on the differentiation of myeloid cells into myeloid-derived suppressor cells (MDSC) and tumor-associated macrophages (TAM), which are known to promote tumorigenesis. The myeloid compartment associated with ETBF-induced colon tumorigenesis in Min mice was defined using flow cytometry and gene expression profiling. Cell sorted immature myeloid cells were functionally assayed for inhibition of T cell proliferation and iNOS expression in order to delineate MDSC populations. A comparison of ETBF infection to that of other oncogenic bacteria (Fusobacterium nucleatum or pks+ E. coli) revealed a specific, ETBF-associated colonic immune infiltrate. ETBF-triggered colon tumorigenesis is associated with an IL-17-driven myeloid signature characterized by subversion of steady-state myelopoiesis in favor of the generation of protumoral monocytic (MO)-MDSCs. Combined action of the Bacteroides fragilis enterotoxin BFT and IL-17 on colonic epithelial cells promoted the differentiation of MO-MDSCs, which selectively upregulated Arg1 and Nos2, produced NO and suppressed T cell proliferation. Evidence of a pathogenic inflammatory signature in humans colonized with ETBF may allow for the identification of populations at risk for developing colon cancer.

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Section: Discussionsupporting

confidence: 93%

The myeloid immune signature of enterotoxigenic Bacteroides fragilis-induced murine colon tumorigenesis

et al. 2017

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“…Previous work has demonstrated that IFNγ promotes tumor development primarily in the early stage of papilloma development 26 . IL-17A, in turn, has a role in the promotion process in both human non-melanoma skin cancer and mouse models of skin cancer, suggesting that Th2- and Th17-type cytokine profile of the T cells lacking FURIN could be driving the carcinogenesis process at later stages 31-33 . LysMcre KO mice, in contrast, display accelerated innate immunity responses, and a heterozygous, inactivating mutation in the FurinA gene results in enhanced innate responses in Mycobacterium marinum –infected zebrafish 19,40 .…”

Section: Discussionmentioning

confidence: 99%

T-cell-expressed proprotein convertase FURIN inhibits DMBA/TPA-induced skin cancer development

et al. 2016

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Proprotein convertases (PCSK) have a critical role in the body homeostasis as enzymes responsible for processing precursor proteins into their mature forms. FURIN, the first characterized member of the mammalian PCSK family, is overexpressed in multiple malignancies and the inhibition of its activity has been considered potential cancer treatment. FURIN has also an important function in the adaptive immunity, since its deficiency in T cells causes an impaired peripheral immune tolerance and accelerates immune responses. We addressed whether deleting FURIN from the immune cells would strengthen anticancer responses by subjecting mouse strains lacking FURIN from either T cells or macrophages and granulocytes to the DMBA/TPA two-stage skin carcinogenesis protocol. Unexpectedly, deficiency of FURIN in T cells resulted in enhanced and accelerated development of tumors, whereas FURIN deletion in macrophages and granulocytes had no effect. The epidermises of T-cell-specific FURIN deficient mice were significantly thicker with more proliferating Ki67+ cells. In contrast, there were no differences in the numbers of the T cells. The flow cytometric analyses of T-cell populations in skin draining lymph nodes showed that FURIN T-cell KO mice have an inherent upregulation of early activation marker CD69 as well as more CD4+CD25+Foxp3+ positive T regulatory cells. In the early phase of tumor promotion, T cells from the T-cell-specific FURIN knockout animals produced more interferon gamma, whereas at later stage the production of Th2- and Th17-type cytokines was more prominent than in wild-type controls. In conclusion, while PCSK inhibitors are promising therapeutics in cancer treatment, our results show that inhibiting FURIN specifically in T cells may promote squamous skin cancer development.

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“…In addition to suppressing antitumour immunity, neutrophils may promote tumour growth by limiting cancer cell senescence 76 , promoting angiogenesis 77 , triggering thrombosis via neutrophil extracellular traps 78 , inducing genotoxic damage 79 and recruiting other tumour-promoting cells 80 . Because it is challenging to distinguish MDSCs from neutrophils and monocytes in both humans and mice 68 , many functions attributed to MDSCs may apply to neutrophils and/or monocytes, and vice versa.…”

Section: Degranulationmentioning

confidence: 99%

The role of myeloid cells in cancer therapies

2016

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Recent clinical trials have demonstrated the ability to durably control cancer in some patients by manipulating T lymphocytes. These immunotherapies are revolutionizing cancer treatment but benefit only a minority of patients. It is thus a crucial time for clinicians, cancer scientists and immunologists to determine the next steps in shifting cancer treatment towards better cancer control. This Review describes recent advances in our understanding of tumour-associated myeloid cells. These cells remain less studied than T lymphocytes but have attracted particular attention because their presence in tumours is often linked to altered patient survival. Also, experimental studies indicate that myeloid cells modulate key cancer-associated activities, including immune evasion, and affect virtually all types of cancer therapy. Consequently, targeting myeloid cells could overcome limitations of current treatment options.

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Immature myeloid cells directly contribute to skin tumor development by recruiting IL-17–producing CD4+ T cells

Abstract: Ortiz et al. report the accumulation of immature myeloid cells in skin tissue of patients with inflammatory conditions, which predisposes to the development of cancer.

Cited by 66 publications

References 60 publications

The myeloid immune signature of enterotoxigenic Bacteroides fragilis-induced murine colon tumorigenesis

The myeloid immune signature of enterotoxigenic Bacteroides fragilis-induced murine colon tumorigenesis

T-cell-expressed proprotein convertase FURIN inhibits DMBA/TPA-induced skin cancer development

The role of myeloid cells in cancer therapies

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