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postgraduate thesis: Tumor associated macrophages reprogramming : the role of TGF-beta/TLR7 and adiponectin

TitleTumor associated macrophages reprogramming : the role of TGF-beta/TLR7 and adiponectin
Authors
Issue Date2015
PublisherThe University of Hong Kong (Pokfulam, Hong Kong)
Citation
Peng, J. [彭佼]. (2015). Tumor associated macrophages reprogramming : the role of TGF-beta/TLR7 and adiponectin. (Thesis). University of Hong Kong, Pokfulam, Hong Kong SAR. Retrieved from http://dx.doi.org/10.5353/th_b5558991
AbstractTumor-associated macrophages (TAMs) play a key role in the escape of tumor cells from immune surveillance. “Re-programming” TAMs to switch from a M2 to a M1-type phenotype and thereby restore tumor specific immune responses that are protective continues stimulate considerable scientific interest in the field of tumor biology. The aims of this study focus on: 1) to identify the inhibition of TGF-β signaling in combination with TLR7 ligation could re-program the phenotype of TAMs and increase their tumoricidal activities; 2) to investigate that adiponectin (APN) deficiency can promote TAMs polarization towards a M1-like phenotype and reduce tumor progression in murine sarcoma model. TGF-β plays a multi-functional role in tumor development including modulating the biological activity of both the tumor and TAMs. In a TAM/tumor cell co-culture system in which both cells were isolated from murine sarcoma model, I found inhibition of TGF-β signaling with TGF-β receptor I inhibitor in combination with TLR7 ligation could re-program TAMs to the M1-like type, evidenced by: 1) up-regulating the expression of M1-like type marker iNOS, CD80 and MHCII in TAMs; 2) down-regulating the expression of VEGF and CD31 to suppress angiogenesis; 3) increasing tumoricidal activity of TAMs and inducing tumor cells apoptosis and 4) elevating infiltration of inflammatory immune cells 〖CD4〗^+,〖 CD8〗^+ T cells and neutrophils in tumor mass. Mechanistically, it was also found that combination treatment could enhance NF-кB activation through up-regulating TRAF6 expression and increasing NF-кB nuclear translocation. APN, anti-inflammatory adipokine, has been shown to promote macrophage polarization to a M2 type in vitro. In the present study, APN and TAMs have high expression in infantile rhabdomyosarcoma, particularly in its malignant subtype. The study was then extended to investigate the effect of APN on TAMs polarization by murine MN/MCA1 sarcoma model. The results showed that exogenous APN had no direct effect on MN/MCA1 proliferation but tumor size was sharply reduced in 〖apn〗^(-/-) mice compared to their wild type counterparts. Next, my study demonstrates that the accumulation of TAMs in 〖apn〗^(-/-) mice was reduced correlated to down-regulation of serum MCP-1. Furthermore, TAMs showed a M1-like phenotype with a marked increase in the 〖MHCII 〗^highpopulation. Quantitative PCR analysis indicated that iNOS was increased, whereas the M2 markers IL-10 and YM1 were decreased. Increased TNF-α and reduced IL-10 were also observed in the serum and TAMs of 〖apn〗^(-/-) mice. In addition, APN deficiency increased frequency of CD4+, CD8+ T cells and NK cells in the tumors and down-regulated MMP-9 and collagen to suppress tumor metastasis. Moreover, p-p38 was sharply decreased in TAMs of 〖apn〗^(-/-) mice and adoption of p38 MAPK inhibitor could significantly reduce tumor size and increase MHCII expression in wild type mice, which suggested that APN regulated p38 MAPK signaling pathway may involve in TAMs polarization. In summary, the present study indicated the plasticity of TAMs which could be re-programmed depending on the alteration of microenvironment. Either inhibition of TGF-β in combination with TLR7 ligation or reducing APN in TAMs could polarize TAMs towards a M1-like type to restrict tumor progression.
DegreeDoctor of Philosophy
SubjectMacrophages
Dept/ProgramSurgery
Persistent Identifierhttp://hdl.handle.net/10722/216268

 

DC FieldValueLanguage
dc.contributor.authorPeng, Jiao-
dc.contributor.author彭佼-
dc.date.accessioned2015-09-08T23:11:35Z-
dc.date.available2015-09-08T23:11:35Z-
dc.date.issued2015-
dc.identifier.citationPeng, J. [彭佼]. (2015). Tumor associated macrophages reprogramming : the role of TGF-beta/TLR7 and adiponectin. (Thesis). University of Hong Kong, Pokfulam, Hong Kong SAR. Retrieved from http://dx.doi.org/10.5353/th_b5558991-
dc.identifier.urihttp://hdl.handle.net/10722/216268-
dc.description.abstractTumor-associated macrophages (TAMs) play a key role in the escape of tumor cells from immune surveillance. “Re-programming” TAMs to switch from a M2 to a M1-type phenotype and thereby restore tumor specific immune responses that are protective continues stimulate considerable scientific interest in the field of tumor biology. The aims of this study focus on: 1) to identify the inhibition of TGF-β signaling in combination with TLR7 ligation could re-program the phenotype of TAMs and increase their tumoricidal activities; 2) to investigate that adiponectin (APN) deficiency can promote TAMs polarization towards a M1-like phenotype and reduce tumor progression in murine sarcoma model. TGF-β plays a multi-functional role in tumor development including modulating the biological activity of both the tumor and TAMs. In a TAM/tumor cell co-culture system in which both cells were isolated from murine sarcoma model, I found inhibition of TGF-β signaling with TGF-β receptor I inhibitor in combination with TLR7 ligation could re-program TAMs to the M1-like type, evidenced by: 1) up-regulating the expression of M1-like type marker iNOS, CD80 and MHCII in TAMs; 2) down-regulating the expression of VEGF and CD31 to suppress angiogenesis; 3) increasing tumoricidal activity of TAMs and inducing tumor cells apoptosis and 4) elevating infiltration of inflammatory immune cells 〖CD4〗^+,〖 CD8〗^+ T cells and neutrophils in tumor mass. Mechanistically, it was also found that combination treatment could enhance NF-кB activation through up-regulating TRAF6 expression and increasing NF-кB nuclear translocation. APN, anti-inflammatory adipokine, has been shown to promote macrophage polarization to a M2 type in vitro. In the present study, APN and TAMs have high expression in infantile rhabdomyosarcoma, particularly in its malignant subtype. The study was then extended to investigate the effect of APN on TAMs polarization by murine MN/MCA1 sarcoma model. The results showed that exogenous APN had no direct effect on MN/MCA1 proliferation but tumor size was sharply reduced in 〖apn〗^(-/-) mice compared to their wild type counterparts. Next, my study demonstrates that the accumulation of TAMs in 〖apn〗^(-/-) mice was reduced correlated to down-regulation of serum MCP-1. Furthermore, TAMs showed a M1-like phenotype with a marked increase in the 〖MHCII 〗^highpopulation. Quantitative PCR analysis indicated that iNOS was increased, whereas the M2 markers IL-10 and YM1 were decreased. Increased TNF-α and reduced IL-10 were also observed in the serum and TAMs of 〖apn〗^(-/-) mice. In addition, APN deficiency increased frequency of CD4+, CD8+ T cells and NK cells in the tumors and down-regulated MMP-9 and collagen to suppress tumor metastasis. Moreover, p-p38 was sharply decreased in TAMs of 〖apn〗^(-/-) mice and adoption of p38 MAPK inhibitor could significantly reduce tumor size and increase MHCII expression in wild type mice, which suggested that APN regulated p38 MAPK signaling pathway may involve in TAMs polarization. In summary, the present study indicated the plasticity of TAMs which could be re-programmed depending on the alteration of microenvironment. Either inhibition of TGF-β in combination with TLR7 ligation or reducing APN in TAMs could polarize TAMs towards a M1-like type to restrict tumor progression.-
dc.languageeng-
dc.publisherThe University of Hong Kong (Pokfulam, Hong Kong)-
dc.relation.ispartofHKU Theses Online (HKUTO)-
dc.rightsThe author retains all proprietary rights, (such as patent rights) and the right to use in future works.-
dc.rightsCreative Commons: Attribution 3.0 Hong Kong License-
dc.subject.lcshMacrophages-
dc.titleTumor associated macrophages reprogramming : the role of TGF-beta/TLR7 and adiponectin-
dc.typePG_Thesis-
dc.identifier.hkulb5558991-
dc.description.thesisnameDoctor of Philosophy-
dc.description.thesislevelDoctoral-
dc.description.thesisdisciplineSurgery-
dc.description.naturepublished_or_final_version-

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