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ELF5 Drives Lung Metastasis in Luminal Breast Cancer through Recruitment of Gr1+ CD11b+ Myeloid-Derived Suppressor Cells.

Gallego-Ortega D, Ledger A, Roden DL, Law AM, Magenau A, Kikhtyak Z, Cho C, Allerdice SL, Lee HJ, Valdes-Mora F, Herrmann D, Salomon R, Young AI, Lee BY, Sergio CM, Kaplan W, Piggin C, Conway JR, Rabinovich B, Millar EK, Oakes SR, Chtanova T, Swarbrick A, Naylor MJ, O'Toole S, Green AR, Timpson P, Gee JM, Ellis IO, Clark SJ, Ormandy CJ - PLoS Biol. (2015)

Bottom Line: Myeloid-derived suppressor cells, a group of immature neutrophils recently identified as mediators of vasculogenesis and metastasis, were recruited to the tumor in response to ELF5.Depletion of these cells using specific Ly6G antibodies prevented ELF5 from driving vasculogenesis and metastasis.Thus, in the MMTV-PyMT mouse mammary model, increased ELF5 levels drive metastasis by co-opting the innate immune system.

View Article: PubMed Central - PubMed

Affiliation: Garvan Institute of Medical Research and The Kinghorn Cancer Centre, Darlinghurst, New South Wales, Australia.

ABSTRACT
During pregnancy, the ETS transcription factor ELF5 establishes the milk-secreting alveolar cell lineage by driving a cell fate decision of the mammary luminal progenitor cell. In breast cancer, ELF5 is a key transcriptional determinant of tumor subtype and has been implicated in the development of insensitivity to anti-estrogen therapy. In the mouse mammary tumor virus-Polyoma Middle T (MMTV-PyMT) model of luminal breast cancer, induction of ELF5 levels increased leukocyte infiltration, angiogenesis, and blood vessel permeability in primary tumors and greatly increased the size and number of lung metastasis. Myeloid-derived suppressor cells, a group of immature neutrophils recently identified as mediators of vasculogenesis and metastasis, were recruited to the tumor in response to ELF5. Depletion of these cells using specific Ly6G antibodies prevented ELF5 from driving vasculogenesis and metastasis. Expression signatures in luminal A breast cancers indicated that increased myeloid cell invasion and inflammation were correlated with ELF5 expression, and increased ELF5 immunohistochemical staining predicted much shorter metastasis-free and overall survival of luminal A patients, defining a group who experienced unexpectedly early disease progression. Thus, in the MMTV-PyMT mouse mammary model, increased ELF5 levels drive metastasis by co-opting the innate immune system. As ELF5 has been previously implicated in the development of antiestrogen resistance, this finding implicates ELF5 as a defining factor in the acquisition of the key aspects of the lethal phenotype in luminal A breast cancer.

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Immune cell subsets within tumors and the effect of depletion of MDSCs on ELF5-driven lung metastases.Panels A and B, tumor content of myeloid or lymphoid lineage immune cell subsets expressed as either a proportion of total tumor cells (after erythrocyte lysis) or as a proportion of CD45+ hematopoietic cells. S5 Fig shows the gating strategy. Panel C, relative proportions of Ly6G and Ly6C MDSC in mice of the indicated genotypes (Ly6G/Ly6C ratio between genotypes are nonsignificant Student’s t test p = 0,886). Panel D, the effect of ELF5 on the proportion of reactive oxygen species (ROS) positive Ly6C or Ly6G cells (LHS panels) or on ROS cellular intensity measured as geometric mean (RHS panels). Nonsignificant p-values are not shown.
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pbio.1002330.g006: Immune cell subsets within tumors and the effect of depletion of MDSCs on ELF5-driven lung metastases.Panels A and B, tumor content of myeloid or lymphoid lineage immune cell subsets expressed as either a proportion of total tumor cells (after erythrocyte lysis) or as a proportion of CD45+ hematopoietic cells. S5 Fig shows the gating strategy. Panel C, relative proportions of Ly6G and Ly6C MDSC in mice of the indicated genotypes (Ly6G/Ly6C ratio between genotypes are nonsignificant Student’s t test p = 0,886). Panel D, the effect of ELF5 on the proportion of reactive oxygen species (ROS) positive Ly6C or Ly6G cells (LHS panels) or on ROS cellular intensity measured as geometric mean (RHS panels). Nonsignificant p-values are not shown.

Mentions: We sought to characterize the ELF5-driven inflammatory phenotype and its effect in metastasis. There is an extensive and persuasive literature regarding the pro-angiogenic and -metastatic roles of innate immune cells in the PyMT model. New drugs targeting the immune system are currently revolutionizing cancer treatment. We examined the recruitment and activation of tumor immune cell infiltrates in response to ELF5 using flow cytometry. We measured myeloid (Fig 6A) and lymphoid (Fig 6B) lineages as a percentage of the remaining total cells, or as a proportion of total CD45+ hematopoietic cells. S5 Fig shows the gating strategy and cell surface markers used to produce this analysis. Among the myeloid populations, MDSCs (defined as Gr-1+CD11b+) showed an increased proportion of either total cells or hematopoietic cells, however no significant changes were observed in the number of the other myeloid populations analyzed (Fig 6A). T- and B-cell lymphoid lineages increased as a proportion of total cells, indicative of increased inflammation (Fig 6B). Proportional with the total leukocyte population, B-cell increase was 1.5-fold higher in ELF5 tumors. Within the leukocyte T CD3+ population, T-CD8+ cell number was significantly decreased (2-fold) but no change was observed in the T-CD4+ population, increasing the T-CD4 to -CD8 cell ratio consistent with a MDSC-driven pro-tumorigenic immune suppressive microenvironment.


ELF5 Drives Lung Metastasis in Luminal Breast Cancer through Recruitment of Gr1+ CD11b+ Myeloid-Derived Suppressor Cells.

Gallego-Ortega D, Ledger A, Roden DL, Law AM, Magenau A, Kikhtyak Z, Cho C, Allerdice SL, Lee HJ, Valdes-Mora F, Herrmann D, Salomon R, Young AI, Lee BY, Sergio CM, Kaplan W, Piggin C, Conway JR, Rabinovich B, Millar EK, Oakes SR, Chtanova T, Swarbrick A, Naylor MJ, O'Toole S, Green AR, Timpson P, Gee JM, Ellis IO, Clark SJ, Ormandy CJ - PLoS Biol. (2015)

Immune cell subsets within tumors and the effect of depletion of MDSCs on ELF5-driven lung metastases.Panels A and B, tumor content of myeloid or lymphoid lineage immune cell subsets expressed as either a proportion of total tumor cells (after erythrocyte lysis) or as a proportion of CD45+ hematopoietic cells. S5 Fig shows the gating strategy. Panel C, relative proportions of Ly6G and Ly6C MDSC in mice of the indicated genotypes (Ly6G/Ly6C ratio between genotypes are nonsignificant Student’s t test p = 0,886). Panel D, the effect of ELF5 on the proportion of reactive oxygen species (ROS) positive Ly6C or Ly6G cells (LHS panels) or on ROS cellular intensity measured as geometric mean (RHS panels). Nonsignificant p-values are not shown.
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Related In: Results  -  Collection

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pbio.1002330.g006: Immune cell subsets within tumors and the effect of depletion of MDSCs on ELF5-driven lung metastases.Panels A and B, tumor content of myeloid or lymphoid lineage immune cell subsets expressed as either a proportion of total tumor cells (after erythrocyte lysis) or as a proportion of CD45+ hematopoietic cells. S5 Fig shows the gating strategy. Panel C, relative proportions of Ly6G and Ly6C MDSC in mice of the indicated genotypes (Ly6G/Ly6C ratio between genotypes are nonsignificant Student’s t test p = 0,886). Panel D, the effect of ELF5 on the proportion of reactive oxygen species (ROS) positive Ly6C or Ly6G cells (LHS panels) or on ROS cellular intensity measured as geometric mean (RHS panels). Nonsignificant p-values are not shown.
Mentions: We sought to characterize the ELF5-driven inflammatory phenotype and its effect in metastasis. There is an extensive and persuasive literature regarding the pro-angiogenic and -metastatic roles of innate immune cells in the PyMT model. New drugs targeting the immune system are currently revolutionizing cancer treatment. We examined the recruitment and activation of tumor immune cell infiltrates in response to ELF5 using flow cytometry. We measured myeloid (Fig 6A) and lymphoid (Fig 6B) lineages as a percentage of the remaining total cells, or as a proportion of total CD45+ hematopoietic cells. S5 Fig shows the gating strategy and cell surface markers used to produce this analysis. Among the myeloid populations, MDSCs (defined as Gr-1+CD11b+) showed an increased proportion of either total cells or hematopoietic cells, however no significant changes were observed in the number of the other myeloid populations analyzed (Fig 6A). T- and B-cell lymphoid lineages increased as a proportion of total cells, indicative of increased inflammation (Fig 6B). Proportional with the total leukocyte population, B-cell increase was 1.5-fold higher in ELF5 tumors. Within the leukocyte T CD3+ population, T-CD8+ cell number was significantly decreased (2-fold) but no change was observed in the T-CD4+ population, increasing the T-CD4 to -CD8 cell ratio consistent with a MDSC-driven pro-tumorigenic immune suppressive microenvironment.

Bottom Line: Myeloid-derived suppressor cells, a group of immature neutrophils recently identified as mediators of vasculogenesis and metastasis, were recruited to the tumor in response to ELF5.Depletion of these cells using specific Ly6G antibodies prevented ELF5 from driving vasculogenesis and metastasis.Thus, in the MMTV-PyMT mouse mammary model, increased ELF5 levels drive metastasis by co-opting the innate immune system.

View Article: PubMed Central - PubMed

Affiliation: Garvan Institute of Medical Research and The Kinghorn Cancer Centre, Darlinghurst, New South Wales, Australia.

ABSTRACT
During pregnancy, the ETS transcription factor ELF5 establishes the milk-secreting alveolar cell lineage by driving a cell fate decision of the mammary luminal progenitor cell. In breast cancer, ELF5 is a key transcriptional determinant of tumor subtype and has been implicated in the development of insensitivity to anti-estrogen therapy. In the mouse mammary tumor virus-Polyoma Middle T (MMTV-PyMT) model of luminal breast cancer, induction of ELF5 levels increased leukocyte infiltration, angiogenesis, and blood vessel permeability in primary tumors and greatly increased the size and number of lung metastasis. Myeloid-derived suppressor cells, a group of immature neutrophils recently identified as mediators of vasculogenesis and metastasis, were recruited to the tumor in response to ELF5. Depletion of these cells using specific Ly6G antibodies prevented ELF5 from driving vasculogenesis and metastasis. Expression signatures in luminal A breast cancers indicated that increased myeloid cell invasion and inflammation were correlated with ELF5 expression, and increased ELF5 immunohistochemical staining predicted much shorter metastasis-free and overall survival of luminal A patients, defining a group who experienced unexpectedly early disease progression. Thus, in the MMTV-PyMT mouse mammary model, increased ELF5 levels drive metastasis by co-opting the innate immune system. As ELF5 has been previously implicated in the development of antiestrogen resistance, this finding implicates ELF5 as a defining factor in the acquisition of the key aspects of the lethal phenotype in luminal A breast cancer.

Show MeSH
Related in: MedlinePlus