title: Delivery of foreign cytotoxic T lymphocyte epitopes to tumor tissues for effective antitumor immunotherapy against pre-established solid tumors in mice.
abstract: Cytotoxic T lymphocyte (CTL) can have remarkable abilities to kill tumor cells. However, the establishment of successful CTL-based anticancer therapy has met with many challenges. Within tumor cells, there exist subpopulations with low or no expression of the targeted antigen (termed as antigen-loss variants). In addition, tumor cells can downregulate the levels of major histocompatibility complex class I (MHC-I) molecules on cell surface due to immune pressure. As a result, some tumor cells can escape the immune pressure bestowed by CTLs, resulting in treatment failure. To address these difficulties, a new approach is developed to deliver foreign high-affinity CTL epitopes to tumor tissues utilizing pH-responsive "smart" microparticles (MPs). These MPs could encapsulate CTL peptide epitope, release the peptide under acidic condition encountered in tumor tissues and enhance CTL activation. Mice bearing pre-established tumor as "antigen-loss variant" solid tumor models were administered intratumorally with MPs containing the CTL peptide, which showed 100% survival following the treatment. In contrast, all control mice died from tumor. Significant protection from tumor-induced death was also observed with systemic administration of CTL peptide-MPs. The therapeutic efficacy can be attributed to enhanced delivery of the epitope to tumor tissues, presentation of the epitope by tumor cells as well as tumor stromal cells and/or generation of epitope-specific CTLs by the peptide-containing MPs. These findings offer a promising new direction for treating established solid tumor using CTL therapy.
authors.affiliation: Department of Chemistry, Michigan State University, 578 S. Shaw Lane, East Lansing, MI, 48824, USA.
authors.forename: Herbert W
authors.initials: HW
authors.lastname: Kavunja
authors.affiliation: Department of Chemistry, Michigan State University, 578 S. Shaw Lane, East Lansing, MI, 48824, USA.
authors.forename: Shuyao
authors.initials: S
authors.lastname: Lang
authors.affiliation: Department of Chemistry, Michigan State University, 578 S. Shaw Lane, East Lansing, MI, 48824, USA.
authors.forename: Suttipun
authors.initials: S
authors.lastname: Sungsuwan
authors.affiliation: Department of Chemistry, Michigan State University, 578 S. Shaw Lane, East Lansing, MI, 48824, USA.
authors.forename: Zhaojun
authors.initials: Z
authors.lastname: Yin
authors.affiliation: Department of Chemistry, Michigan State University, 578 S. Shaw Lane, East Lansing, MI, 48824, USA. xuefei@chemistry.msu.edu.
authors.forename: Xuefei
authors.identifier: http://orcid.org/0000-0002-6468-5526
authors.initials: X
authors.lastname: Huang
mesh_terms: D000230:Adenocarcinoma / Q000276:immunology / Q000628:therapy*; D000818:Animals; D045744:Cell Line, Tumor; D018984:Epitopes, T-Lymphocyte / Q000008:administration & dosage* / Q000737:chemistry; D005260:Female; D006801:Humans; D006863:Hydrogen-Ion Concentration; D007167:Immunotherapy / Q000379:methods*; D008081:Liposomes / Q000008:administration & dosage* / Q000737:chemistry; D008213:Lymphocyte Activation; D008223:Lymphoma / Q000276:immunology / Q000628:therapy*; D051379:Mice; D008810:Mice, Inbred C57BL; D009368:Neoplasm Transplantation; D009374:Neoplasms, Experimental; D010455:Peptides / Q000008:administration & dosage* / Q000737:chemistry; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology*; D019139:Tumor Escape
chemical_list: D018984:Epitopes, T-Lymphocyte; D008081:Liposomes; D010455:Peptides
keywords: Cytotoxic T cells; Epitope delivery; Immunotherapy; Microparticles; Solid tumor