title: Intratumoral peptide injection enhances tumor cell antigenicity recognized by cytotoxic T lymphocytes: a potential option for improvement in antigen-specific cancer immunotherapy.
abstract: Antigen-specific cancer immunotherapy is a promising strategy for improving cancer treatment. Recently, many tumor-associated antigens and their epitopes recognized by cytotoxic T lymphocytes (CTLs) have been identified. However, the density of endogenously presented antigen-derived peptides on tumor cells is generally sparse, resulting in the inability of antigen-specific CTLs to work effectively. We hypothesize that increasing the density of an antigen-derived peptide would enhance antigen-specific cancer immunotherapy. Here, we demonstrated that intratumoral peptide injection leads to additional peptide loading onto major histocompatibility complex class I molecules of tumor cells, enhancing tumor cell recognition by antigen-specific CTLs. In in vitro studies, human leukocyte antigen (HLA)-A*02:01-restricted glypican-3144-152 (FVGEFFTDV) and cytomegalovirus495-503 (NLVPMVATV) peptide-specific CTLs showed strong activity against all peptide-pulsed cell lines, regardless of whether the tumor cells expressed the antigen. In in vivo studies using immunodeficient mice, glypican-3144-152 and cytomegalovirus495-503 peptides injected into a solid mass were loaded onto HLA class I molecules of tumor cells. In a peptide vaccine model and an adoptive cell transfer model using C57BL/6 mice, intratumoral injection of ovalbumin257-264 peptide (SIINFEKL) was effective for tumor growth inhibition and survival against ovalbumin-negative tumors without adverse reactions. Moreover, we demonstrated an antigen-spreading effect that occurred after intratumoral peptide injection. Intratumoral peptide injection enhances tumor cell antigenicity and may be a useful option for improvement in antigen-specific cancer immunotherapy against solid tumors.
authors.affiliation: Division of Cancer Immunotherapy, Research Center for Innovative Oncology, National Cancer Center Hospital East, 6-5-1 Kashiwanoha, Kashiwa, 277-8577, Japan.
authors.forename: Daisuke
authors.initials: D
authors.lastname: Nobuoka
authors.forename: Toshiaki
authors.initials: T
authors.lastname: Yoshikawa
authors.forename: Mari
authors.initials: M
authors.lastname: Takahashi
authors.forename: Tatsuaki
authors.initials: T
authors.lastname: Iwama
authors.forename: Kazutaka
authors.initials: K
authors.lastname: Horie
authors.forename: Manami
authors.initials: M
authors.lastname: Shimomura
authors.forename: Shiro
authors.initials: S
authors.lastname: Suzuki
authors.forename: Noriko
authors.initials: N
authors.lastname: Sakemura
authors.forename: Munehide
authors.initials: M
authors.lastname: Nakatsugawa
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Sadamori
authors.forename: Takahito
authors.initials: T
authors.lastname: Yagi
authors.forename: Toshiyoshi
authors.initials: T
authors.lastname: Fujiwara
authors.forename: Tetsuya
authors.initials: T
authors.lastname: Nakatsura
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D003110:Colonic Neoplasms / Q000276:immunology / Q000628:therapy; D018984:Epitopes, T-Lymphocyte / Q000276:immunology*; D005260:Female; D015234:HLA-A Antigens / Q000276:immunology*; D056945:Hep G2 Cells; D006801:Humans; D007167:Immunotherapy / Q000379:methods*; D015552:Injections, Intralesional; D008113:Liver Neoplasms / Q000276:immunology / Q000628:therapy; D008223:Lymphoma / Q000276:immunology / Q000628:therapy; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D008822:Mice, Transgenic; D010446:Peptide Fragments / Q000008:administration & dosage* / Q000276:immunology*; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology*
chemical_list: D018984:Epitopes, T-Lymphocyte; D015234:HLA-A Antigens; D010446:Peptide Fragments