Enhanced antitumor activity of a novel, oral, helper epitope-containing WT1 protein vaccine in a model of murine leukemia

• Published in: BMC cancer Vol. 23; no. 1; p. 167
• Main Authors: Minagawa, Hikaru, Hashii, Yoshiko, Nakajima, Hiroko, Fujiki, Fumihiro, Morimoto, Soyoko, Nakata, Jun, Shirakawa, Toshiro, Katayama, Takane, Tsuboi, Akihiro, Ozono, Keiichi
• Format: Journal Article
• Language: English
• Published: England BioMed Central Ltd 20.02.2023; BioMed Central; BMC
• Subjects: Amino acids; Analysis; Animals; Antigens; Antitumor activity; Cancer Vaccines; Care and treatment; CD3 antigen; CD4 antigen; CD4+ T cell help; CD8 antigen; CD8-Positive T-Lymphocytes; Cell-mediated immunity; Cloning; Cytotoxicity; Diagnosis; Dosage and administration; Effector memory T cells; Epitopes; Female; Flow cytometry; Immune response; Immunization; Immunotherapy; Inoculation; Interferon; Interferon-gamma; Kidney Neoplasms; Leukemia; Lymphocytes; Lymphocytes T; Mice; Mice, Inbred C57BL; Mouse leukemia complex; Oral administration; Oral vaccine; Patient outcomes; Peptides; Peripheral blood; Phenotypes; Proteins; Splenocytes; Stem cells; T-Lymphocytes, Cytotoxic; Tumor cells; Tumor-infiltrating lymphocytes; Tumors; Vaccines; Wilms Tumor; WT1 protein; WT1 Proteins; WT1-specific cytotoxic T cells; γ-Interferon; Japan; St Louis Missouri; United States > US; Effector memory T cells; Intestinal immunity; WT1 protein; CD4+ T cell help; Tumor-infiltrating lymphocytes; Murine leukemia; Immunotherapy; Oral vaccine; WT1-specific cytotoxic T cells
• ISSN: 1471-2407; 1471-2407
• DOI: 10.1186/s12885-023-10547-5

A Wilms' tumor 1 (WT1) oral vaccine, Bifidobacterium longum (B. longum) 420, in which the bacterium is used as a vector for WT1 protein, triggers immune responses through cellular immunity consisting of cytotoxic T lymphocytes (CTLs) and other immunocompetent cells (e.g., helper T cells). We developed a novel, oral, helper epitope-containing WT1 protein vaccine (B. longum 2656) to examine whether or not B. longum 420/2656 combination further accelerates the CD4 T cell help-enhanced antitumor activity in a model of murine leukemia. C1498-murine WT1-a genetically-engineered, murine leukemia cell line to express murine WT1-was used as tumor cell. Female C57BL/6 J mice were allocated to the B. longum 420, 2656, and 420/2656 combination groups. The day of subcutaneous inoculation of tumor cells was considered as day 0, and successful engraftment was verified on day 7. The oral administration of the vaccine by gavage was initiated on day 8. Tumor volume, the frequency and phenotypes of WT1-specific CTLs in CD8 T cells in peripheral blood (PB) and tumor-infiltrating lymphocytes (TILs), as well as the proportion of interferon-gamma (INF-γ)-producing CD3 CD4 T cells pulsed with WT1 peptide in splenocytes and TILs were determined. Tumor volume was significantly smaller (p < 0.01) in the B. longum 420/2656 combination group than in the B. longum 420 group on day 24. WT1-specific CTL frequency in CD8 T cells in PB was significantly greater in the B. longum 420/2656 combination group than in the B. longum 420 group at weeks 4 (p < 0.05) and 6 (p < 0.01). The proportion of WT1-specific, effector memory CTLs in PB increased significantly in the B. longum 420/2656 combination group than in the B. longum 420 group at weeks 4 and 6 (p < 0.05 each). WT1-specific CTL frequency in intratumoral CD8 T cells and the proportion of IFN-γ-producing CD3 CD4 T cells in intratumoral CD4 T cells increased significantly (p < 0.05 each) in the B. longum 420/2656 combination group than in the 420 group. B. longum 420/2656 combination further accelerated antitumor activity that relies on WT1-specific CTLs in the tumor compared with B. longum 420.