TY - JOUR
T1 - Mesothelin Virus-Like Particle Immunization Controls Pancreatic Cancer Growth through CD8+ T Cell Induction and Reduction in the Frequency of CD4+foxp3+ICOS- Regulatory T Cells
AU - Zhang, Sheng
AU - Yong, Lin Kin
AU - Li, Dali
AU - Cubas, Rafael
AU - Chen, Changyi
AU - Yao, Qizhi
PY - 2013/7/9
Y1 - 2013/7/9
N2 - Our previous study has shown that mesothelin (MSLN) is a potential immunotherapeutic target for pancreatic cancer. Here, we further studied the immunogenicity of chimeric murine MSLN-virus-like particles (mMSLN-VLPs), their ability to break tolerance to mMSLN, a self-antigen, and deciphered the mechanism of immune responses elicited by mMSLN-VLP immunization using a pancreatic cancer (PC) mouse model. In addition to what we have found with xenogeneic human MSLN-VLP (hMSLN-VLP), mMSLN-VLP immunization was able to break the tolerance to intrinsic MSLN and mount mMSLN-specific, cytotoxic CD8+ T cells which led to a significant reduction in tumor volume and prolonged survival in an orthotopic PC mouse model. Furthermore, CD4+foxp3+ regulatory T cells (Tregs) were progressively decreased in both spleen and tumor tissues following mMSLN-VLP immunization and this was at least partly due to elevated levels of IL-6 production from activated plasmocytoid dendritic cell (pDC)-like cells following mMSLN-VLP immunization. Moreover, mMSLN-VLP treatment mainly reduced the frequency of the CD4+foxp3+ICOS- Treg subset. However, mMSLN-VLP induced IL-6 production also increased ICOSL expression on pDC-like cells which supported the proliferation of immunosuppressive CD4+foxp3+ICOS+ Treg cells. This study reveals that mMSLN-VLP immunization is capable of controlling PC progression by effectively mounting an immune response against mMSLN, a tumor self-antigen, and altering the immunosuppressive tumor microenvironment via activation of pDCs-like cells and reduction in the frequency of CD4+foxp3+ICOS- Treg cells. However, combination therapies will likely need to be used in order to target residual CD4+foxp3+ICOS+ Treg cells.
AB - Our previous study has shown that mesothelin (MSLN) is a potential immunotherapeutic target for pancreatic cancer. Here, we further studied the immunogenicity of chimeric murine MSLN-virus-like particles (mMSLN-VLPs), their ability to break tolerance to mMSLN, a self-antigen, and deciphered the mechanism of immune responses elicited by mMSLN-VLP immunization using a pancreatic cancer (PC) mouse model. In addition to what we have found with xenogeneic human MSLN-VLP (hMSLN-VLP), mMSLN-VLP immunization was able to break the tolerance to intrinsic MSLN and mount mMSLN-specific, cytotoxic CD8+ T cells which led to a significant reduction in tumor volume and prolonged survival in an orthotopic PC mouse model. Furthermore, CD4+foxp3+ regulatory T cells (Tregs) were progressively decreased in both spleen and tumor tissues following mMSLN-VLP immunization and this was at least partly due to elevated levels of IL-6 production from activated plasmocytoid dendritic cell (pDC)-like cells following mMSLN-VLP immunization. Moreover, mMSLN-VLP treatment mainly reduced the frequency of the CD4+foxp3+ICOS- Treg subset. However, mMSLN-VLP induced IL-6 production also increased ICOSL expression on pDC-like cells which supported the proliferation of immunosuppressive CD4+foxp3+ICOS+ Treg cells. This study reveals that mMSLN-VLP immunization is capable of controlling PC progression by effectively mounting an immune response against mMSLN, a tumor self-antigen, and altering the immunosuppressive tumor microenvironment via activation of pDCs-like cells and reduction in the frequency of CD4+foxp3+ICOS- Treg cells. However, combination therapies will likely need to be used in order to target residual CD4+foxp3+ICOS+ Treg cells.
UR - http://www.scopus.com/inward/record.url?scp=84879953494&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=84879953494&partnerID=8YFLogxK
U2 - 10.1371/journal.pone.0068303
DO - 10.1371/journal.pone.0068303
M3 - Article
C2 - 23874581
AN - SCOPUS:84879953494
SN - 1932-6203
VL - 8
JO - PloS one
JF - PloS one
IS - 7
M1 - e68303
ER -