Human lung adenocarcinoma CD47 is upregulated by interferon-γ and promotes tumor metastasis

Abstract

Tumor cells can evade attack by phagocytes by upregulating the self-marker CD47. The mechanisms underlying tumor CD47 upregulation, however, remain unclear. Here, we report that human lung adenocarcinoma CD47 is upregulated by interferon-γ (IFN-γ), the level in the tumor microenvironment of which is markedly increased after tumor metastasis and chemotherapy. The IFN-γ receptor is expressed in various human lung adenocarcinoma tissues regardless of the CD47 protein expression, and lung adenocarcinoma CD47 expression is significantly enhanced following tumor metastasis or chemotherapy treatment. In line with this, CD47 expression in various lung cancer cells is markedly increased by IFN-γ treatment. Mechanistically, IFN-γ promotes CD47 expression by activating interferon regulatory factor-1 (IRF-1), which binds to an IRF-1-binding domain within the CD47 promoter region and increases CD47 transcription. Functionally, IFN-γ-enhanced CD47 expression facilitates human lung cancer cell invasion both in vitro and in vivo, whereas IFN-γ-induced CD47 upregulation and cancer metastasis are blocked by mutating the IRF-1-binding site within the CD47 promoter. Our results reveal IFN-γ-enhanced CD47 expression as a novel mechanism promoting human lung adenocarcinoma progression. Tumor cells can evade attack by phagocytes by upregulating the self-marker CD47. The mechanisms underlying tumor CD47 upregulation, however, remain unclear. Here, we report that human lung adenocarcinoma CD47 is upregulated by interferon-γ (IFN-γ), the level in the tumor microenvironment of which is markedly increased after tumor metastasis and chemotherapy. The IFN-γ receptor is expressed in various human lung adenocarcinoma tissues regardless of the CD47 protein expression, and lung adenocarcinoma CD47 expression is significantly enhanced following tumor metastasis or chemotherapy treatment. In line with this, CD47 expression in various lung cancer cells is markedly increased by IFN-γ treatment. Mechanistically, IFN-γ promotes CD47 expression by activating interferon regulatory factor-1 (IRF-1), which binds to an IRF-1-binding domain within the CD47 promoter region and increases CD47 transcription. Functionally, IFN-γ-enhanced CD47 expression facilitates human lung cancer cell invasion both in vitro and in vivo, whereas IFN-γ-induced CD47 upregulation and cancer metastasis are blocked by mutating the IRF-1-binding site within the CD47 promoter. Our results reveal IFN-γ-enhanced CD47 expression as a novel mechanism promoting human lung adenocarcinoma progression. IntroductionMetastasis is the primary underlying cause of mortality in lung cancer patients. For a primary lung tumor to successfully metastasize, it must possess two important characteristics: the ability to avoid destruction by the immune system and a considerable migratory capacity. Previous studies have demonstrated that CD47 is an important molecule that can modulate both events, promoting immune evasion by initiating signal regulatory protein α (SIRPα)-mediated inhibitory signaling in immune cells1Jaiswal S. Chao M.P. Majeti R. Weissman I.L. Macrophages as mediators of tumor immunosurveillance.Trends Immunol. 2010; 31: 212-219https://doi.org/10.1016/j.it.2010.04.001Abstract Full Text Full Text PDF PubMed Scopus (178) Google Scholar and facilitating tumor cell migration as an adhesion molecule.2Matozaki T. Murata Y. Okazawa H. Ohnishi H. Functions and molecular mechanisms of the CD47-SIRP alpha signalling pathway.Trends Cell Biol. 2009; 19: 72-80https://doi.org/10.1016/j.tcb.2008.12.001Abstract Full Text Full Text PDF PubMed Scopus (302) Google Scholar On the one hand, as a new immune checkpoint molecule,3Liu X.J. Kwon H. Li Z.H. Fu Y.X. Is CD47 an innate immune checkpoint for tumor evasion?.J. Hematol. Oncol. 2017; 10: 12https://doi.org/10.1186/s13045-016-0381-zCrossref PubMed Scopus (110) Google Scholar CD47 binds to SIRPα on the phagocyte surface and initiates inhibitory signaling to prevent phagocytosis of tumor cells by phagocytes.4Veillette A. Chen J. SIRPα–CD47 immune checkpoint blockade in anticancer therapy.Trends Immunol. 2018; 39: 173-184https://doi.org/10.1016/j.it.2017.12.005Abstract Full Text Full Text PDF PubMed Scopus (184) Google Scholar,5Barclay A.N. Van den Berg T.K. The interaction between signal regulatory protein alpha (SIRPα) and CD47: structure, function, and therapeutic target.Annu. Rev. Immunol. 2014; 32: 25-50https://doi.org/10.1146/annurev-immunol-032713-120142Crossref PubMed Scopus (427) Google Scholar Exploiting CD47-SIRPα signaling has been proven to be an effective way for cancers to evade immune attack by phagocytes. Blockade of CD47 alone via antibodies or fusion proteins or in combination with other antitumor reagents shows great potential in the treatment of various cancers.6Zhang X.Y. Fan J.J. Wang S.F. Li Y.B. Wang Y.C. Li S. Luan J.Y. Wang Z.Y. Song P. Chen Q.C. et al.Targeting CD47 and autophagy elicited enhanced antitumor effects in non-small cell lung cancer.Cancer Immunol. Res. 2017; 5: 363-375https://doi.org/10.1158/2326-6066.Cir-16-0398Crossref PubMed Google Scholar, 7Cui Z.L. Xu D.F. Zhang F.F. Sun J.Y. Song L. Ye W.J. Zeng J.X. Zhou Zhang CD47 blockade therapeutic of lung in a Cell Res. PubMed Scopus Google Scholar, X.Y. Wang Y.C. Fan J.J. Chen Luan J.Y. Wang S.F. Li Y.B. Ye L. Li S. et CD47 therapeutic effects of in non-small cell lung PubMed Scopus Google Scholar On the other hand, CD47 is an in cell migration and T. H. Wang Zhou Zhang Y. Song Y. J. et CD47 signal and promotes cancer cell and 10: PubMed Scopus Google Scholar, A. et a in by of and Biol. PubMed Scopus Google Scholar, Y. A. of by CD47 with signal regulatory protein Immunol. PubMed Scopus Google Scholar CD47 blockade significantly the of CD47 with and cell migration and Y. The of CD47 in Biol. Full Text Full Text PDF PubMed Scopus Google Scholar the of CD47 in facilitating both tumor immune evasion and CD47 expression is upregulated in various tumor cells and to tumor Zhang Y. Y. H. Li Y. H. Chen of CD47 and expression in with non-small cell lung Res. PubMed Scopus Google Scholar, Y. Li J. Chen X.Y. J. Wang CD47 expression is an for in non-small cell lung 5: Full Text Full Text PDF PubMed Scopus Google Scholar, A. L. P. et between CD47 expression, and in with non-small cell lung cancer.Cancer PubMed Scopus Google Scholar the upregulation of CD47 in lung a new that the of receptor cells CD47 to lung cancer cell metastasis in has been cells cancer cells and the expression in lung cancer cell Immunol. Res. Scopus Google Scholar the mechanism underlying CD47 upregulation in tumor cells Zhang et H. H. L. Zhang J. CD47 expression in cancer cells to evasion of phagocytosis and of cancer A. PubMed Scopus Google Scholar that CD47 expression in cancer cells to phagocytosis that to the upregulation of CD47 expression in other cancers or cancer cells a by et Y. et signalling to CD47 upregulation in 2017; PubMed Scopus Google Scholar that a signaling to CD47 upregulation in a of cancer possess CD47 with immune checkpoint et L. Li Y. R. S. the antitumor immune CD47 and PubMed Scopus Google Scholar that the expression of both CD47 and be by that the a that is in human the upregulation of CD47 expression in cancers with has demonstrated that CD47 expression can be by to a in the CD47 promoter and that the upregulation of CD47 expression as of the mechanism of tumor J. T.K. CD47 promotes and blockade the of in in PubMed Scopus Google Scholar that signaling is with CD47 upregulation in tumor cells to chemotherapy a IFN-γ has been as an antitumor that tumor via immune H. The of in tumor and cancer Rev. PubMed Scopus Google Scholar that IFN-γ is by level in the tumor microenvironment is increased following cell chemotherapy or S. T. P. J.J. et and cell to 2018; Full Text Full Text PDF PubMed Scopus Google H. Fu Y.X. and a Rev. Oncol. 2017; PubMed Scopus Google Scholar the of the of IFN-γ in anticancer has been the has been that IFN-γ both and in of the and in and cancer Rev. Immunol. 2018; PubMed Scopus Google The two of in Res. PubMed Scopus Google Scholar IFN-γ expression can cell the and antitumor immune Y. 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Kwon H. Li Z.H. Fu Y.X. Is CD47 an innate immune checkpoint for tumor evasion?.J. Hematol. 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Y. of human lung Full Text Full Text PDF PubMed Scopus Google Scholar cells and cells the of the after the the which cells or cells two one IFN-γ and the other as a IFN-γ the to tumor and The of tumor cells in various by both and an CD47 CD47 human tumor cells of the and other with the CD47 human lung cancer cell and metastasis in by both and of human CD47 and IFN-γ treatment markedly tumor in the tumor metastasis the to the In CD47 blocked the and metastasis of by results that IFN-γ promotes human lung cancer metastasis by tumor CD47 promotes human lung cancer cell metastasis in by upregulating cells and in the of the the with IFN-γ and the other IFN-γ as the to tumor and and and human CD47 immune in and In both and of tumor as studies have the upregulation of CD47 in various and the between CD47 level and tumor A. L. P. et between CD47 expression, and in with non-small cell lung cancer.Cancer PubMed Scopus Google M.P. S. et with to phagocytosis and 2010; Full Text Full Text PDF PubMed Scopus Google Scholar the mechanisms underlying the tumor cell CD47 upregulation remain In are or CD47 In human lung adenocarcinoma tissues and various lung cancer we that CD47 are markedly increased following tumor metastasis or chemotherapy and both with the of IFN-γ in the that CD47 upregulation in R. Chao M.P. S. Weissman I.L. CD47 is an and therapeutic on human 2009; Full Text Full Text PDF PubMed Scopus Google Scholar, P. Wang J. H. R. et regulatory protein alpha interaction is a therapeutic for human A. PubMed Scopus Google Scholar, Xu Z.H. Zhang L. A. L. of CD47 tumor and lung Full Text Full Text PDF PubMed Scopus Google Scholar the mechanism underlying tumor CD47 upregulation be a mechanism by various studies have that CD47 expression in cancer cells can be enhanced by or H. H. L. Zhang J. CD47 expression in cancer cells to evasion of phagocytosis and of cancer A. PubMed Scopus Google Y. et signalling to CD47 upregulation in 2017; PubMed Scopus Google Scholar mechanisms to other tumor cells or cancer cells various In as a by IFN-γ has been in the and level is increased following cancer metastasis or chemotherapy S. T. P. J.J. et and cell to 2018; Full Text Full Text PDF PubMed Scopus Google and PubMed Scopus Google cells and PubMed Scopus Google Scholar an in CD47 expression by IFN-γ as a mechanism underlying the upregulation of cancer CD47 In line with this, the upregulation of CD47 by the by Ye et in and Z.H. Xu Chen Y.C. Chen J.J. of CD47 expression by in cancer Oncol. PubMed Scopus Google Scholar the of IFN-γ-induced CD47 in tumor that IFN-γ and CD47 T. H. Wang Zhou Zhang Y. Song Y. J. et CD47 signal and promotes cancer cell and 10: PubMed Scopus Google L. A. J. R. et promotes in cancer via Res. PubMed Google Scholar, Zhang R. and tumor and metastasis via of Immunol. PubMed Scopus Google Scholar, H. Wang J.X. Li Y.B. Y. Y.B. Z.H. et promotes tumor invasion and metastasis in non-small cell lung PubMed Scopus Google Scholar IFN-γ can the expression of in tumor A. J. H. Sun L. Wang X.Y. et receptor signaling and 2017; 19: Full Text Full Text PDF PubMed Scopus Google Scholar the of CD47 and by IFN-γ the of IFN-γ antitumor the of IFN-γ on cancer cell CD47 we that various human lung regardless of the CD47 protein expression expressed IFN-γ Our that IFN-γ cancer cell CD47 expression, which in promotes cancer the of IFN-γ in tumor results with the that IFN-γ a promoting or tumor the of the as and H. and prevent primary and PubMed Scopus Google Scholar, A. A. J. S. S. A. T. et by cells increases to tumor and 2018; Full Text Full Text PDF PubMed Scopus Google Scholar, P. R. lung by cells in with enhanced expression of A. PubMed Scopus Google to as a molecule to phagocyte CD47 is an adhesion molecule with protein and Cell Biol. Full Text Full Text PDF PubMed Scopus Google Scholar CD47 has been to in cell migration and A. CD47 for migration Cell Biol. PubMed Scopus Google Scholar Blockade of CD47 via antibodies or fusion proteins can Y. The of CD47 in Biol. Full Text Full Text PDF PubMed Scopus Google Scholar studies that in to phagocyte SIRPα to prevent cell phagocytosis by den Berg T.K. The CD47-SIRP alpha signaling as an innate immune checkpoint in Rev. 2017; PubMed Scopus Google Scholar CD47 can to other adhesion or signaling to cell adhesion and the mechanism underlying cell migration it the of CD47 with cell surface or of various signaling and and cell S. CD47 signaling and to Rev. Biol. PubMed Scopus Google Scholar In the we both in vitro and in to the of CD47 by IFN-γ in human lung cancer cell migration and CD47 tumor cell migration in vitro and metastasis of human lung adenocarcinoma the to the in results an of CD47 on promoting tumor cell In the that human lung adenocarcinoma CD47 expression is upregulated by IFN-γ activating CD47 and upregulated CD47 expression by IFN-γ promotes human lung cancer and lung adenocarcinoma and lung of lung adenocarcinoma and after tumor metastasis to the of lung adenocarcinoma tissues and after chemotherapy and lung adenocarcinoma with metastasis the of the in and The of the are in of the and of the in with the of of the of and the of and by the of human lung cancer cell and the of Cell of and in in Cell with and of the cells in a with cell human lung cancer cancer cell human tumor by and the tumor and for following the The cell a the cells and the cell with in and The following the cells with and to IFN-γ for On the cells for on of following the tissues in and with with to proteins of as the CD47 and IFN-γ as as the in and on For the CD47 expression of as and the of cells as and is and of as expression, A. T. et of and CD47 is a novel for of cancer 2014; 5: PubMed Scopus Google Scholar by two in a The of CD47 and IFN-γ in cancer and with cell in the cells to IFN-γ for after the cells On the cells and with the cells with a on for and by an for cell to the expression of CD47 on the surface of cancer on the of cells with and with antibodies CD47 or Cell by with antibodies and of the with for For a and to as a The are in to the expression of as a For the CD47 promoter the site by the the of the site of the The CD47 promoter the by with that the region to be the CD47 promoter The as CD47 CD47 and The and cells to the and protein after and by and following the antibodies CD47 Cell and with an the system For of cell with to CD47 with a and for with and expression cells and to the The for in a expression on a system The of by following the the in a of of of and of and of The with an for by of for and for The are in of the in and the as an cells in for and in to the with of and of the for of in and cells the and to the and the to the and in the on a system The for the CD47 promoter as and of CD47 cells with system to CD47 human CD47 and in The for the CD47 as the the and in cells to the CD47 cells with for in the of cells in and with to CD47 migration migration an after and in The cells to the and to the The for in an the the cells that the surface of the with for The with and with in for The cells on the surface of the with a The by and the cells in the of and and CD47 cells the of cells in The the of the and a the with cells of the with of other and the other the of the after the to the and The tissues in for The for and or for CD47 or of the and by the of of the for and migration are of and in and are as the between by and by for The of the between CD47 expression and and by the or the for The as and as and IntroductionMetastasis is the primary underlying cause of mortality in lung cancer patients. For a primary lung tumor to successfully metastasize, it must possess two important characteristics: the ability to avoid destruction by the immune system and a considerable migratory capacity. Previous studies have demonstrated that CD47 is an important molecule that can modulate both events, promoting immune evasion by initiating signal regulatory protein α (SIRPα)-mediated inhibitory signaling in immune cells1Jaiswal S. Chao M.P. Majeti R. Weissman I.L. Macrophages as mediators of tumor immunosurveillance.Trends Immunol. 2010; 31: 212-219https://doi.org/10.1016/j.it.2010.04.001Abstract Full Text Full Text PDF PubMed Scopus (178) Google Scholar and facilitating tumor cell migration as an adhesion molecule.2Matozaki T. Murata Y. Okazawa H. Ohnishi H. Functions and molecular mechanisms of the CD47-SIRP alpha signalling pathway.Trends Cell Biol. 2009; 19: 72-80https://doi.org/10.1016/j.tcb.2008.12.001Abstract Full Text Full Text PDF PubMed Scopus (302) Google Scholar On the one hand, as a new immune checkpoint molecule,3Liu X.J. Kwon H. Li Z.H. Fu Y.X. Is CD47 an innate immune checkpoint for tumor evasion?.J. Hematol. Oncol. 2017; 10: 12https://doi.org/10.1186/s13045-016-0381-zCrossref PubMed Scopus (110) Google Scholar CD47 binds to SIRPα on the phagocyte surface and initiates inhibitory signaling to prevent phagocytosis of tumor cells by phagocytes.4Veillette A. Chen J. SIRPα–CD47 immune checkpoint blockade in anticancer therapy.Trends Immunol. 2018; 39: 173-184https://doi.org/10.1016/j.it.2017.12.005Abstract Full Text Full Text PDF PubMed Scopus (184) Google Scholar,5Barclay A.N. Van den Berg T.K. The interaction between signal regulatory protein alpha (SIRPα) and CD47: structure, function, and therapeutic target.Annu. Rev. Immunol. 2014; 32: 25-50https://doi.org/10.1146/annurev-immunol-032713-120142Crossref PubMed Scopus (427) Google Scholar Exploiting CD47-SIRPα signaling has been proven to be an effective way for cancers to evade immune attack by phagocytes. Blockade of CD47 alone via antibodies or fusion proteins or in combination with other antitumor reagents shows great potential in the treatment of various cancers.6Zhang X.Y. Fan J.J. Wang S.F. Li Y.B. Wang Y.C. Li S. Luan J.Y. Wang Z.Y. Song P. Chen Q.C. et al.Targeting CD47 and autophagy elicited enhanced antitumor effects in non-small cell lung cancer.Cancer Immunol. Res. 2017; 5: 363-375https://doi.org/10.1158/2326-6066.Cir-16-0398Crossref PubMed Google Scholar, 7Cui Z.L. Xu D.F. Zhang F.F. Sun J.Y. Song L. Ye W.J. Zeng J.X. Zhou Zhang CD47 blockade therapeutic of lung in a Cell Res. PubMed Scopus Google Scholar, X.Y. Wang Y.C. Fan J.J. Chen Luan J.Y. Wang S.F. Li Y.B. Ye L. Li S. et CD47 therapeutic effects of in non-small cell lung PubMed Scopus Google Scholar On the other hand, CD47 is an in cell migration and T. H. Wang Zhou Zhang Y. Song Y. J. et CD47 signal and promotes cancer cell and 10: PubMed Scopus Google Scholar, A. et a in by of and Biol. PubMed Scopus Google Scholar, Y. A. of by CD47 with signal regulatory protein Immunol. PubMed Scopus Google Scholar CD47 blockade significantly the of CD47 with and cell migration and Y. The of CD47 in Biol. Full Text Full Text PDF PubMed Scopus Google Scholar the of CD47 in facilitating both tumor immune evasion and CD47 expression is upregulated in various tumor cells and to tumor Zhang Y. Y. H. Li Y. H. Chen of CD47 and expression in with non-small cell lung Res. PubMed Scopus Google Scholar, Y. Li J. Chen X.Y. J. Wang CD47 expression is an for in non-small cell lung 5: Full Text Full Text PDF PubMed Scopus Google Scholar, A. L. P. et between CD47 expression, and in with non-small cell lung cancer.Cancer PubMed Scopus Google Scholar the upregulation of CD47 in lung a new that the of receptor cells CD47 to lung cancer cell metastasis in has been cells cancer cells and the expression in lung cancer cell Immunol. Res. Scopus Google Scholar the mechanism underlying CD47 upregulation in tumor cells Zhang et H. H. L. Zhang J. CD47 expression in cancer cells to evasion of phagocytosis and of cancer A. PubMed Scopus Google Scholar that CD47 expression in cancer cells to phagocytosis that to the upregulation of CD47 expression in other cancers or cancer cells a by et Y. et signalling to CD47 upregulation in 2017; PubMed Scopus Google Scholar that a signaling to CD47 upregulation in a of cancer possess CD47 with immune checkpoint et L. Li Y. R. S. the antitumor immune CD47 and PubMed Scopus Google Scholar that the expression of both CD47 and be by that the a that is in human the upregulation of CD47 expression in cancers with has demonstrated that CD47 expression can be by to a in the CD47 promoter and that the upregulation of CD47 expression as of the mechanism of tumor J. T.K. CD47 promotes and blockade the of in in PubMed Scopus Google Scholar that signaling is with CD47 upregulation in tumor cells to chemotherapy a IFN-γ has been as an antitumor that tumor via immune H. The of in tumor and cancer Rev. PubMed Scopus Google Scholar that IFN-γ is by level in the tumor microenvironment is increased following cell chemotherapy or S. T. P. J.J. et and cell to 2018; Full Text Full Text PDF PubMed Scopus Google H. Fu Y.X. and a Rev. Oncol. 2017; PubMed Scopus Google Scholar the of the of IFN-γ in anticancer has been the has been that IFN-γ both and in of the and in and cancer Rev. Immunol. 2018; PubMed Scopus Google The two of in Res. PubMed Scopus Google Scholar IFN-γ expression can cell the and antitumor immune Y. Van L. is for of PubMed Scopus Google Scholar In studies that IFN-γ can the expression of cell protein a immune checkpoint molecule on the surface of tumor the of to cell protein on cells to cell IFN-γ signaling tumor cell antitumor cell tumor cell and cancer with immune checkpoint on interferon Full Text Full Text PDF PubMed Scopus Google Scholar that CD47 is a immune checkpoint molecule we that IFN-γ by upregulating tumor cell CD47 the we report that CD47 expression in various human lung and cells can be by IFN-γ and that CD47 upregulation by IFN-γ is with tumor Our an regulatory factor-1 domain within the CD47 promoter region and shows that level in the is following tumor metastasis or can CD47 expression by activating The effects of IFN-γ on human lung adenocarcinoma CD47 expression and cancer metastasis in with human lung cancer Our results reveal that human lung adenocarcinoma can IFN-γ to CD47 expression metastasis and chemotherapy treatment.

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