Purpose: The atypical chemokine receptor 2 (ACKR2) is a scavenger receptor for most infl ammatory CC chemokines. It plays a protective role in chronic infl ammation, autoimmunity and infl ammation-related cancer. The aim of this project is to investigate the role of ACKR2 in primary tumor development and metastatization in different mouse model. Methods: NeuT mice (overexpressing the rat oncogene Her2) crossed with ACKR2-/-mice, orthotopic and intravenous injection of the breast carcinoma cell line 4T1 in Wild Type (WT) and ACKR2-/- Balb/c mice and intravenous injection of the melanoma cell line B16F10 in WT and ACKR2-/- C57BL/6 mice. Tumors and metastasis were studied with in hematoxylin and eosin and immunohistochemistry analysis; blood composition and metastatic organ infi ltrate were studied with FACS analysis. Neutrophil phenotype was investigated with FACS and qPCR analysis. Results: Tumor arising in ACKR2-/- NeuT mice showed a more aggressive phenotype when compared to WT NeuT mice. On the contrary, ACKR2-/- NeuT mice were protected from spontaneous lung metastasis. Metastasis protection was registered also using the 4T1 orthotopic model. FACS analysis indicated an increase of Ly6G+ polymorphonuclear cells and Ly6Chigh monocytes in the blood and in the pre-metastatic lungs of ACKR2-/-mice. Depletion experiments demonstrated that neutrophils are implied in metastasis protection. Moreover, ACKR2-/- neutrophils express an activated phenotype, increased levels of the chemokine receptor CCR2 and have increased CCR2 dependent cytotoxic activity. Discussion: ACKR2 is described to regulate leukocytes recruitment shaping chemokine in tissues but our evidences indicate ACKR2 as a direct regulator of immune cells activity. Conclusion: These results indicate that ACKR2 expression has a dual but opposite role in tumor, inhibiting primary tumor growth but promoting lung metastatization trough the inhibition of anti-metastatic neutrophils.
Atypical chemokine receptor 2 promote metastatization inhibiting neutrophil recruitment and activation / M. Massara, O. Bonavita, B. Savino, V. Mollica Poeta, E. Setten, N. Caronni, C. Recordati, M. Sironi, A. Mantovani, M. Locati, R. Bonecchi. ((Intervento presentato al convegno International Retreat of PhD Students in Immunology tenutosi a Napoli nel 2016.
Atypical chemokine receptor 2 promote metastatization inhibiting neutrophil recruitment and activation
M. MassaraPrimo
;O. BonavitaSecondo
;E. Setten;N. Caronni;C. Recordati;M. LocatiPenultimo
;R. BonecchiUltimo
2016
Abstract
Purpose: The atypical chemokine receptor 2 (ACKR2) is a scavenger receptor for most infl ammatory CC chemokines. It plays a protective role in chronic infl ammation, autoimmunity and infl ammation-related cancer. The aim of this project is to investigate the role of ACKR2 in primary tumor development and metastatization in different mouse model. Methods: NeuT mice (overexpressing the rat oncogene Her2) crossed with ACKR2-/-mice, orthotopic and intravenous injection of the breast carcinoma cell line 4T1 in Wild Type (WT) and ACKR2-/- Balb/c mice and intravenous injection of the melanoma cell line B16F10 in WT and ACKR2-/- C57BL/6 mice. Tumors and metastasis were studied with in hematoxylin and eosin and immunohistochemistry analysis; blood composition and metastatic organ infi ltrate were studied with FACS analysis. Neutrophil phenotype was investigated with FACS and qPCR analysis. Results: Tumor arising in ACKR2-/- NeuT mice showed a more aggressive phenotype when compared to WT NeuT mice. On the contrary, ACKR2-/- NeuT mice were protected from spontaneous lung metastasis. Metastasis protection was registered also using the 4T1 orthotopic model. FACS analysis indicated an increase of Ly6G+ polymorphonuclear cells and Ly6Chigh monocytes in the blood and in the pre-metastatic lungs of ACKR2-/-mice. Depletion experiments demonstrated that neutrophils are implied in metastasis protection. Moreover, ACKR2-/- neutrophils express an activated phenotype, increased levels of the chemokine receptor CCR2 and have increased CCR2 dependent cytotoxic activity. Discussion: ACKR2 is described to regulate leukocytes recruitment shaping chemokine in tissues but our evidences indicate ACKR2 as a direct regulator of immune cells activity. Conclusion: These results indicate that ACKR2 expression has a dual but opposite role in tumor, inhibiting primary tumor growth but promoting lung metastatization trough the inhibition of anti-metastatic neutrophils.Pubblicazioni consigliate
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