Mi et al. developed an attenuated Salmonella typhimurium strain that harbored a quorum-sensing synchronized lysis circuit (SLC) and overexpressed LIGHT. Intragastric SLCVNP20009 treatment colonized tumors to mediate intratumoral lysis and locally release LIGHT. In mouse CRC models, SLCVNP20009 expanded CD4+ and CD8+ cells, cDCs, and group 3 intestinal innate lymphoid cells (ILC3) critical for mucosal host/microbe interactions, promoted formation and maturation of tertiary lymphoid structures (mTLS), and inhibited tumor growth. Fewer mTLSs and reduced survival were observed in tumor-bearing mice deficient in ILC3 or LIGHT receptor HVEM.
Contributed by Paula Hochman
ABSTRACT: The efficacy of immunotherapy in colorectal cancer (CRC) hinges upon a comprehensive understanding of how the immune system interacts with tumor cells within the colorectal microenvironment. Mature tertiary lymphoid structures (mTLSs) are associated with an increased objective response rate, progression-free survival, and overall survival in patients with CRC. Thus, it has been suggested that increasing mTLSs in the context of CRC could improve patient outcomes. However, no established method to specifically induce TLS maturation within and around tumor sites is available. To address this gap in technology, we engineered a Salmonella typhimurium strain, SLC(VNP20009), to express tumor necrosis factor (TNF) superfamily member 14 (TNFSF14, also called LIGHT). This strain colonized tumors and released LIGHT, which then formed a ligand-receptor pair with herpes virus entry mediator (HVEM) to induce a powerful cellular immune response. Furthermore, this engineered microbe modulated the proportions of intestinal innate lymphoid cells (ILCs), which serve an anti-infection role in innate immunity. Mice that were deficient in HVEM or ILC3 exhibited fewer mTLSs, a greater bacterial burden, and increased mortality in two different models of CRC. Thus, this engineered microbe with enhanced immunogenic properties demonstrated the potential to stimulate mTLS-associated antitumor immune responses in the colon and was well tolerated in vivo. Our results indicate that LIGHT-HVEM signaling on group 3 ILCs (ILC3s) is crucial for mTLS formation and T cell-mediated antitumor immunity in CRC and additionally suggest a synbiotic-based therapeutic approach for the management of CRC.
Author Info: (1) Department of Radiology, Third Xiangya Hospital, Central South University, Changsha, Hunan 410013, China. (2) Department of Radiology, Third Xiangya Hospital, Central South Uni
Author Info: (1) Department of Radiology, Third Xiangya Hospital, Central South University, Changsha, Hunan 410013, China. (2) Department of Radiology, Third Xiangya Hospital, Central South University, Changsha, Hunan 410013, China. (3) Department of Radiology, Third Xiangya Hospital, Central South University, Changsha, Hunan 410013, China. (4) Department of Radiology, Third Xiangya Hospital, Central South University, Changsha, Hunan 410013, China. (5) Department of Radiology, Third Xiangya Hospital, Central South University, Changsha, Hunan 410013, China. (6) Department of Radiology, Third Xiangya Hospital, Central South University, Changsha, Hunan 410013, China. (7) Department of Radiology, Third Xiangya Hospital, Central South University, Changsha, Hunan 410013, China. (8) Department of Diagnostic Radiology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 119074, Singapore. Department of Chemical and Biomolecular Engineering and Department of Biomedical Engineering, College of Design and Engineering, National University of Singapore, Singapore 117575, Singapore. Department of Pharmacy and Pharmaceutical Sciences, National University of Singapore, Singapore 117544, Singapore. Clinical Imaging Research Centre, Centre for Translational Medicine, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 117599, Singapore. Nanomedicine Translational Research Program, NUS Center for Nanomedicine, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 117597, Singapore. Institute of Molecular and Cell Biology, Agency for Science, Technology, and Research (A*STAR), Singapore 138673, Singapore. Theranostics Center of Excellence (TCE), Yong Loo Lin School of Medicine, National University of Singapore, Singapore 138667, Singapore. (9) Department of Radiology, Third Xiangya Hospital, Central South University, Changsha, Hunan 410013, China. Key Laboratory of Biological Nanotechnology of National Health Commission, Changsha, Hunan 410008, China. Furong Laboratory, Changsha, Hunan 410008, China.
