Tumor‐secreted products repress B‐cell lymphopoiesis in a murine model of breast cancer

Moreau, Joshua M.; Mielnik, Michael; Berger, Alexandra; Furlonger, Caren; Paige, Christopher J.

doi:10.1002/eji.201646552

Cited by 8 publications

(7 citation statements)

References 23 publications

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“…Cancer growing at distant sites can remotely affect BM hematopoiesis by inhibiting B-cell lymphopoiesis and skewing the differentiation of precursor cells toward myelopoiesis (44).…”

Section: Discussionmentioning

confidence: 99%

Tumor-Derived Thymic Stromal Lymphopoietin Expands Bone Marrow B-cell Precursors in Circulation to Support Metastasis

et al. 2019

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Immature B cells in the bone marrow emigrate into the spleen during adult lymphopoiesis. Here, we report that emigration is shifted to earlier B-cell stages in mice with orthotopic breast cancer, spontaneous ovarian cancer, and possibly in human breast carcinoma. Using mouse and human bone marrow aspirates and mouse models challenged with highly metastatic 4T1 breast cancer cells, we demonstrated that this was the result of secretion of thymic stromal lymphopoietin (TSLP) by cancer cells. First, TSLP downregulated surface expression of bone marrow (BM) retention receptors CXCR4 and VLA4 in B-cell precursors, increasing their motility and, presumably, emigration. Then, TSLP sup-ported peripheral survival and proliferation of BM B-cell precursors such as pre-B-like cells. 4T1 cancer cells used the increased pool of circulating pre-B-like cells to generate metastasis-supporting regulatory B cells. As such, the loss of TSLP expression in cancer cells alone or TSLPR deficiency in B cells blocked both accumulation of pre-B-like cells in circulation and cancer metastasis, implying that the pre-B cell-TSLP axis can be an attractive therapeutic target.Significance: Cancer cells induce premature emigration of B-cell precursors from the bone marrow to generate regulatory B cells.

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“…Cancer growing at distant sites can remotely affect BM hematopoiesis by inhibiting B-cell lymphopoiesis and skewing the differentiation of precursor cells toward myelopoiesis (44).…”

Section: Discussionmentioning

confidence: 99%

Tumor-Derived Thymic Stromal Lymphopoietin Expands Bone Marrow B-cell Precursors in Circulation to Support Metastasis

et al. 2019

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“…Furthermore, Il7 expression was also significantly downregulated in mice transplanted with BCR-ABL + preB cells, such that it reduced by ~ 3-fold the production of non-leukemic host B cell progenitors, whereas myeloid cells were only reduced by ~ 20% (82). The inhibitory effect of leukemic cells in host B cell development is not exclusive to B cell leukemias as other types of cancers include solid tumors had similar inhibitory effects in B and NK cell development (111,112). It is tempting to speculate that leukemic cells and other tumors might explore homeostatic mechanisms of growth factor production to turn-off the development of highly proliferative hematopoietic progenitor cells as a strategy for reducing competition for, for example, anabolic nutrients.…”

Section: -Niches For B Lymphopoiesis In Bone Marrowmentioning

confidence: 99%

Cell circuits and niches controlling B cell development

Zehentmeier

Pereira

2019

Immunological Reviews

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Studies over the last decade uncovered overlapping niches for hematopoietic stem cells (HSCs), multipotent progenitor cells, common lymphoid progenitors, and early B cell progenitors. HSC and lymphoid niches are predominantly composed by mesenchymal progenitor cells (MPCs), and by a small subset of endothelial cells. Niche cells create specialized microenvironments through the concomitant production of short-range acting cell-fate determining cytokines such as Interleukin (IL)-7 and Stem Cell Factor (SCF) and the potent chemoattractant C-X-C Motif Chemokine Ligand 12 (CXCL12). This type of cellular organization allows for the cross-talk between hematopoietic stem and progenitor cells with niche cells, such that niche cell activity can be regulated by the quality and quantity of hematopoietic progenitors being produced. For example, pre-leukemic B cell progenitors and preB acute lymphoblastic leukemias interact directly with MPCs, and downregulate IL-7 expression and the production of non-leukemic lymphoid cells. In this review, we discuss a novel model of B cell development that is centered on cellular circuits formed between B cell progenitors and lymphopoietic niches.

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“…Similar to what was observed in T cells, B cells in TDLNs also undergo reprogramming in their transcriptional profiles that reflect phenotypes of suppressed immunity and decreased proliferation. In support of these notions, it was reported that tumors of MMTV-PyMT mice may secrete molecules to inhibit B-cell proliferation and maturation directly, 42 and the noncanonical NF-κB pathway is well known for its role in B cell maturation. 43 The expression profiles of a number of identified DEGs for B cells were shown as in Figures 4c and 4d .…”

Section: Decrease Of Marginal Zone B Cells In Tdlnsmentioning

confidence: 90%

Single-cell analysis reveals immune modulation and metabolic switch in tumor-draining lymph nodes

Chen

et al. 2020

OncoImmunology

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Lymph-node metastasis is a prognosis factor for poor clinical outcome of breast cancer patients. Currently, how breast cancer cells establish pre-metastatic niche in the tumor-draining lymph nodes (TDLNs) is still unclear. To address this question, we isolated heterogeneous cells including immune and stromal cells from naive lymph nodes (LNs) of the FVB/NJ mice and TDLNs of the MMTV-PyMT mice. Single-cell RNA sequencing was performed to investigate the transcriptome of the cells and various bioinformatics analyses were used to identify the altered pathways. Our results revealed several significant changes between naïve LNs and TDLNs. First, according to immunologic signature and pathway analysis, CD4+ and CD8 + T cells showed upregulated angiogenesis pathway genes and higher regulatory T (Treg)-associated genes while they demonstrated downregulation of interferon response and inflammatory response gene signatures, concurrently suggesting an immunosuppressive microenvironment in the TDLNs. Second, profiling of B cells showed down-regulation of marginal zone B lymphocytes in the TDLNs, which was validated by flow cytometric analysis. Third, we found the enhancement of oxidative phosphorylation pathway in the fibroblastic reticular cells (FRCs) of the MMTV-PyMT mice and the elevation of related genes including Prdx3, Ndufa4 and Uqcrb, suggesting massive ATP consumption and TCA cycle metabolism in the FRCs. Collectively, our results reveal the reprogramming of TDLNs during breast cancer progression at single-cell level in a spontaneous breast cancer model and suggest the changes in immune modulation and metabolic switch are key alterations in the preparation of pre-metastatic niche by breast cancer cells.

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Tumor‐secreted products repress B‐cell lymphopoiesis in a murine model of breast cancer

Cited by 8 publications

References 23 publications

Tumor-Derived Thymic Stromal Lymphopoietin Expands Bone Marrow B-cell Precursors in Circulation to Support Metastasis

Tumor-Derived Thymic Stromal Lymphopoietin Expands Bone Marrow B-cell Precursors in Circulation to Support Metastasis

Cell circuits and niches controlling B cell development

Single-cell analysis reveals immune modulation and metabolic switch in tumor-draining lymph nodes

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