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Myeloid expression of angiotensin-converting enzyme facilitates myeloid maturation and inhibits the development of myeloid-derived suppressor cells.

Shen XZ, Okwan-Duodu D, Blackwell WL, Ong FS, Janjulia T, Bernstein EA, Fuchs S, Alkan S, Bernstein KE - Lab. Invest. (2014)

Bottom Line: Here, we show that ACE expression correlates with myeloid maturation in vitro.Forced ACE overexpression in monocytic cells reduces the generation of MDSCs.Thus, manipulating myeloid ACE activity can interfere with MDSC development and the maturation of myeloid cells.

View Article: PubMed Central - PubMed

Affiliation: 1] Division of Immunology, Department of Biomedical Science, Cedars-Sinai Medical Center, Los Angeles, CA, USA [2] Department of Pathology and Laboratory Medicine, Cedars-Sinai Medical Center, Los Angeles, CA, USA.

ABSTRACT
Myeloid-derived suppressor cells (MDSCs) are a heterogeneous population of immature myeloid cells which accumulate in cancer, infection and chronic inflammation. These cells suppress T-cell function and the immune response. Angiotensin-converting enzyme (ACE) is a peptidase that is now known to regulate aspects of myelopoiesis. Here, we show that ACE expression correlates with myeloid maturation in vitro. Forced ACE overexpression in monocytic cells reduces the generation of MDSCs. In vivo, mice with a genetic change resulting in myeloid cell ACE overexpression have reduced numbers of blood and splenic MDSCs in a tumor model and in a model of chronic inflammation induced by complete Freund's adjuvant. In contrast, ACE- mice produce large numbers of MDSCs during chronic inflammation. Macrophages from mice with myeloid ACE overexpressing are more pro-inflammatory and have more tumor-killing activity than cells from wild-type mice. Thus, manipulating myeloid ACE activity can interfere with MDSC development and the maturation of myeloid cells.

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ACE over-expression disrupts the myeloid suppressing environment in cancer. a. WT and ACE 10/10 mice were challenged intradermally with melanoma cells. 14 days later, tumors were dissected and weighed. Here and in 3B, data from individual mice, as well as the group means and SEM are shown. *** P<0.001. b. WT and ACE 10/10 mice were challenged i.v. with 5 × 105 B16-F10 melanoma cells. 14 days later, metastatic nodules in the lungs were counted (top). * P<0.02. A representative photo of the lungs from a WT and ACE 10/10 mouse is shown (bottom). c. Splenocytes from naïve and tumor bearing WT, ACE 10/10, and ACE 10/10 mice treated with the ACE inhibitor captopril were stained for CD11b and Gr1 and analyzed by flow cytometry. CD11b+Gr1intermediate MDSCs are indicated in the boxed area (top). The number of MDSC from individual mice are shown (bottom), as well as the group means and SEM. * P< 0.05, ** P< 0.01. d. Mice were depleted of macrophages by i.p. injection of liposome clodronate or liposome PBS for one week before tumor challenge, and then every 72 h. A group of ACE 10/10 mice were also treated with captopril. All mice were challenged with an intradermal injection of B16-F10. Tumor volume was measured on day 14. While macrophage depletion reduces tumor size in WT mice, it results in larger tumors in ACE 10/10 mice. * P<0.05, ** P<0.01, *** P<0.001. e. Thioglycollate elicited peritoneal macrophages or tumor associated macrophages (TAM) were seeded in 96-well plates. Triplicate wells were primed overnight with 1 µg/ml LPS or left untreated, and then co-cultured with 2 × 104 tumor cells. 18 h later, tumor cell death was evaluated by measuring LDH release into the supernatant. *P< 0.05, ** P<0.02, ns = not significant.
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Figure 3: ACE over-expression disrupts the myeloid suppressing environment in cancer. a. WT and ACE 10/10 mice were challenged intradermally with melanoma cells. 14 days later, tumors were dissected and weighed. Here and in 3B, data from individual mice, as well as the group means and SEM are shown. *** P<0.001. b. WT and ACE 10/10 mice were challenged i.v. with 5 × 105 B16-F10 melanoma cells. 14 days later, metastatic nodules in the lungs were counted (top). * P<0.02. A representative photo of the lungs from a WT and ACE 10/10 mouse is shown (bottom). c. Splenocytes from naïve and tumor bearing WT, ACE 10/10, and ACE 10/10 mice treated with the ACE inhibitor captopril were stained for CD11b and Gr1 and analyzed by flow cytometry. CD11b+Gr1intermediate MDSCs are indicated in the boxed area (top). The number of MDSC from individual mice are shown (bottom), as well as the group means and SEM. * P< 0.05, ** P< 0.01. d. Mice were depleted of macrophages by i.p. injection of liposome clodronate or liposome PBS for one week before tumor challenge, and then every 72 h. A group of ACE 10/10 mice were also treated with captopril. All mice were challenged with an intradermal injection of B16-F10. Tumor volume was measured on day 14. While macrophage depletion reduces tumor size in WT mice, it results in larger tumors in ACE 10/10 mice. * P<0.05, ** P<0.01, *** P<0.001. e. Thioglycollate elicited peritoneal macrophages or tumor associated macrophages (TAM) were seeded in 96-well plates. Triplicate wells were primed overnight with 1 µg/ml LPS or left untreated, and then co-cultured with 2 × 104 tumor cells. 18 h later, tumor cell death was evaluated by measuring LDH release into the supernatant. *P< 0.05, ** P<0.02, ns = not significant.

Mentions: To study the role of ACE over-expression in myeloid maturation and tumor immunology, ACE 10/10 and WT mice were challenged with B16-F10 melanoma cells by subcutaneous injection of tumor cells. Consistent with our previous data,17 two weeks after B16 cell implantation, the resulting tumors in ACE 10/10 mice were significantly smaller (as determined by weight) than those in equivalently treated WT mice (ACE 10/10: 0.71 ± 0.14 g; WT: 1.38 ± 0.13 g, P<0.001, Figure 3a).


Myeloid expression of angiotensin-converting enzyme facilitates myeloid maturation and inhibits the development of myeloid-derived suppressor cells.

Shen XZ, Okwan-Duodu D, Blackwell WL, Ong FS, Janjulia T, Bernstein EA, Fuchs S, Alkan S, Bernstein KE - Lab. Invest. (2014)

ACE over-expression disrupts the myeloid suppressing environment in cancer. a. WT and ACE 10/10 mice were challenged intradermally with melanoma cells. 14 days later, tumors were dissected and weighed. Here and in 3B, data from individual mice, as well as the group means and SEM are shown. *** P<0.001. b. WT and ACE 10/10 mice were challenged i.v. with 5 × 105 B16-F10 melanoma cells. 14 days later, metastatic nodules in the lungs were counted (top). * P<0.02. A representative photo of the lungs from a WT and ACE 10/10 mouse is shown (bottom). c. Splenocytes from naïve and tumor bearing WT, ACE 10/10, and ACE 10/10 mice treated with the ACE inhibitor captopril were stained for CD11b and Gr1 and analyzed by flow cytometry. CD11b+Gr1intermediate MDSCs are indicated in the boxed area (top). The number of MDSC from individual mice are shown (bottom), as well as the group means and SEM. * P< 0.05, ** P< 0.01. d. Mice were depleted of macrophages by i.p. injection of liposome clodronate or liposome PBS for one week before tumor challenge, and then every 72 h. A group of ACE 10/10 mice were also treated with captopril. All mice were challenged with an intradermal injection of B16-F10. Tumor volume was measured on day 14. While macrophage depletion reduces tumor size in WT mice, it results in larger tumors in ACE 10/10 mice. * P<0.05, ** P<0.01, *** P<0.001. e. Thioglycollate elicited peritoneal macrophages or tumor associated macrophages (TAM) were seeded in 96-well plates. Triplicate wells were primed overnight with 1 µg/ml LPS or left untreated, and then co-cultured with 2 × 104 tumor cells. 18 h later, tumor cell death was evaluated by measuring LDH release into the supernatant. *P< 0.05, ** P<0.02, ns = not significant.
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Related In: Results  -  Collection

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getmorefigures.php?uid=PMC4221240&req=5

Figure 3: ACE over-expression disrupts the myeloid suppressing environment in cancer. a. WT and ACE 10/10 mice were challenged intradermally with melanoma cells. 14 days later, tumors were dissected and weighed. Here and in 3B, data from individual mice, as well as the group means and SEM are shown. *** P<0.001. b. WT and ACE 10/10 mice were challenged i.v. with 5 × 105 B16-F10 melanoma cells. 14 days later, metastatic nodules in the lungs were counted (top). * P<0.02. A representative photo of the lungs from a WT and ACE 10/10 mouse is shown (bottom). c. Splenocytes from naïve and tumor bearing WT, ACE 10/10, and ACE 10/10 mice treated with the ACE inhibitor captopril were stained for CD11b and Gr1 and analyzed by flow cytometry. CD11b+Gr1intermediate MDSCs are indicated in the boxed area (top). The number of MDSC from individual mice are shown (bottom), as well as the group means and SEM. * P< 0.05, ** P< 0.01. d. Mice were depleted of macrophages by i.p. injection of liposome clodronate or liposome PBS for one week before tumor challenge, and then every 72 h. A group of ACE 10/10 mice were also treated with captopril. All mice were challenged with an intradermal injection of B16-F10. Tumor volume was measured on day 14. While macrophage depletion reduces tumor size in WT mice, it results in larger tumors in ACE 10/10 mice. * P<0.05, ** P<0.01, *** P<0.001. e. Thioglycollate elicited peritoneal macrophages or tumor associated macrophages (TAM) were seeded in 96-well plates. Triplicate wells were primed overnight with 1 µg/ml LPS or left untreated, and then co-cultured with 2 × 104 tumor cells. 18 h later, tumor cell death was evaluated by measuring LDH release into the supernatant. *P< 0.05, ** P<0.02, ns = not significant.
Mentions: To study the role of ACE over-expression in myeloid maturation and tumor immunology, ACE 10/10 and WT mice were challenged with B16-F10 melanoma cells by subcutaneous injection of tumor cells. Consistent with our previous data,17 two weeks after B16 cell implantation, the resulting tumors in ACE 10/10 mice were significantly smaller (as determined by weight) than those in equivalently treated WT mice (ACE 10/10: 0.71 ± 0.14 g; WT: 1.38 ± 0.13 g, P<0.001, Figure 3a).

Bottom Line: Here, we show that ACE expression correlates with myeloid maturation in vitro.Forced ACE overexpression in monocytic cells reduces the generation of MDSCs.Thus, manipulating myeloid ACE activity can interfere with MDSC development and the maturation of myeloid cells.

View Article: PubMed Central - PubMed

Affiliation: 1] Division of Immunology, Department of Biomedical Science, Cedars-Sinai Medical Center, Los Angeles, CA, USA [2] Department of Pathology and Laboratory Medicine, Cedars-Sinai Medical Center, Los Angeles, CA, USA.

ABSTRACT
Myeloid-derived suppressor cells (MDSCs) are a heterogeneous population of immature myeloid cells which accumulate in cancer, infection and chronic inflammation. These cells suppress T-cell function and the immune response. Angiotensin-converting enzyme (ACE) is a peptidase that is now known to regulate aspects of myelopoiesis. Here, we show that ACE expression correlates with myeloid maturation in vitro. Forced ACE overexpression in monocytic cells reduces the generation of MDSCs. In vivo, mice with a genetic change resulting in myeloid cell ACE overexpression have reduced numbers of blood and splenic MDSCs in a tumor model and in a model of chronic inflammation induced by complete Freund's adjuvant. In contrast, ACE- mice produce large numbers of MDSCs during chronic inflammation. Macrophages from mice with myeloid ACE overexpressing are more pro-inflammatory and have more tumor-killing activity than cells from wild-type mice. Thus, manipulating myeloid ACE activity can interfere with MDSC development and the maturation of myeloid cells.

Show MeSH
Related in: MedlinePlus