title: 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.
abstract: 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.
authors.affiliation: Molecular Surgeon Research Center, Michael E. DeBakey Department of Surgery, Baylor College of Medicine, Houston, Texas, United States of America.
authors.forename: Sheng
authors.initials: S
authors.lastname: Zhang
authors.forename: Lin-Kin
authors.initials: LK
authors.lastname: Yong
authors.forename: Dali
authors.initials: D
authors.lastname: Li
authors.forename: Rafael
authors.initials: R
authors.lastname: Cubas
authors.forename: Changyi
authors.initials: C
authors.lastname: Chen
authors.forename: Qizhi
authors.initials: Q
authors.lastname: Yao
mesh_terms: D000818:Animals; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology* / Q000378:metabolism; D045744:Cell Line, Tumor; D003713:Dendritic Cells / Q000276:immunology / Q000378:metabolism; D004195:Disease Models, Animal; D051858:Forkhead Transcription Factors / Q000378:metabolism; D058851:GPI-Linked Proteins / Q000276:immunology*; D006801:Humans; D060889:Inducible T-Cell Co-Stimulator Protein / Q000378:metabolism; D015850:Interleukin-6 / Q000378:metabolism; D016246:Lymphocytes, Tumor-Infiltrating / Q000276:immunology / Q000378:metabolism; D000090204:Mesothelin; D051379:Mice; D010190:Pancreatic Neoplasms / Q000276:immunology* / Q000378:metabolism / Q000401:mortality / Q000473:pathology*; D050378:T-Lymphocytes, Regulatory / Q000276:immunology* / Q000378:metabolism; D014611:Vaccination; D058425:Vaccines, Virus-Like Particle / Q000276:immunology*; D023041:Xenograft Model Antitumor Assays
chemical_list: C418974:FOXP3 protein, human; D051858:Forkhead Transcription Factors; D058851:GPI-Linked Proteins; D060889:Inducible T-Cell Co-Stimulator Protein; D015850:Interleukin-6; C000715527:MSLN protein, human; C000715528:Msln protein, mouse; D058425:Vaccines, Virus-Like Particle; D000090204:Mesothelin