Ying Zhang (전남대학교 의과대학) | 한빛사논문 > 한빛사

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Ying ZhangYing Zhang

전남대학교 의과대학

Biomaterials, 2023 Apr 27;298:12213 | https://doi.org/10.1016/j.biomaterials.2023.122135 Synergistic cancer immunotherapy utilizing programmed Salmonella typhimurium secreting heterologous flagellin B conjugated to interleukin-15 proteins

Ying Zhang ^a,b, Wenzhi Tan ^c, Rukhsora D. Sultonova ^a,b, Dinh-Huy Nguyen ^a,b, Jin Hai Zheng ^g, Sung-Hwan You^d, Joon Haeng Rhee^e, So-young Kim^a, Koemchhoy Khim ^e, Yeongjin Hong ^a,e, Jung-Joon Min ^a,b,f

^aInstitute for Molecular Imaging and Theranostics, Chonnam National University Medical School, Gwangju, 61469, Republic of Korea
^bDepartment of Molecular Medicine (BrainKorea21 Plus), Chonnam National University Graduate School, Gwangju, 61469, Republic of Korea
^cSchool of Food Science and Bioengineering, Changsha University of Science & Technology, Changsha, Hunan, 410114, China
^dCNCure Biotech, Inc, Republic of Korea
^eDepartment of Microbiology, Chonnam National University Medical School, Hwasun, 58128, Republic of Korea
^fDepartment of Nuclear Medicine, Chonnam National University Medical School and Hwasun Hospital, Hwasun, 58128, Republic of Korea
^gSchool of Biomedical Sciences, Hunan University, Changsha, Hunan, 410082, China

Corresponding authors: Yeongjin Hong, Jung-Joon Min

Abstract

The use of appropriately designed immunotherapeutic bacteria is an appealing approach to tumor therapy because the bacteria specifically target tumor tissue and deliver therapeutic payloads. The present study describes the engineering of an attenuated strain of Salmonella typhimurium deficient in ppGpp biosynthesis (SAM) that could secrete Vibrio vulnificus flagellin B (FlaB) conjugated to human (hIL15/FlaB) and mouse (mIL15/FlaB) interleukin-15 proteins in the presence of L-arabinose (L-ara). These strains, named SAMphIF and SAMpmIF, respectively, secreted fusion proteins that retained bioactivity of both FlaB and IL15. SAMphIF and SAMpmIF inhibited the growth of MC38 and CT26 subcutaneous (sc) tumors in mice and increased mouse survival rate more efficiently than SAM expressing FlaB alone (SAMpFlaB) or IL15 alone (SAMpmIL15 and SAMphIL15), although SAMpmIF had slightly greater antitumor activity than SAMphIF. The mice treated with these bacteria showed enhanced macrophage phenotype shift, from M2-like to M1-like, as well as greater proliferation and activation of CD4+ T, CD8+ T, NK, and NKT cells in tumor tissues. After tumor eradication by these bacteria, ≥50% of the mice show no evidence of tumor recurrence upon rechallenge with the same tumor cells, indicating that they had acquired long-term immune memory. Treatment of mice of 4T1 and B16F10 highly malignant sc tumors with a combination of these bacteria and an immune checkpoint inhibitor, anti-PD-L1 antibody, significantly suppressed tumor metastasis and increased mouse survival rate. Taken together, these findings suggest that SAM secreting IL15/FlaB is a novel therapeutic candidate for bacterial-mediated cancer immunotherapy and that its antitumor activity is enhanced by combination with anti-PD-L1 antibody.

논문정보

형식Research article
게재일2023년 04월 (BRIC 등록일 2023-05-19)
연구진국내(교신)+국외 연구진
분야 의약학 > 응용의학

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