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      Bacteria-based immunotherapy for cancer: a systematic review of preclinical studies

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          Abstract

          Immunotherapy has been emerging as a powerful strategy for cancer management. Recently, accumulating evidence has demonstrated that bacteria-based immunotherapy including naive bacteria, bacterial components, and bacterial derivatives, can modulate immune response via various cellular and molecular pathways. The key mechanisms of bacterial antitumor immunity include inducing immune cells to kill tumor cells directly or reverse the immunosuppressive microenvironment. Currently, bacterial antigens synthesized as vaccine candidates by bioengineering technology are novel antitumor immunotherapy. Especially the combination therapy of bacterial vaccine with conventional therapies may further achieve enhanced therapeutic benefits against cancers. However, the clinical translation of bacteria-based immunotherapy is limited for biosafety concerns and non-uniform production standards. In this review, we aim to summarize immunotherapy strategies based on advanced bacterial therapeutics and discuss their potential for cancer management, we will also propose approaches for optimizing bacteria-based immunotherapy for facilitating clinical translation.

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          Most cited references238

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          Commensal Bifidobacterium promotes antitumor immunity and facilitates anti-PD-L1 efficacy.

          T cell infiltration of solid tumors is associated with favorable patient outcomes, yet the mechanisms underlying variable immune responses between individuals are not well understood. One possible modulator could be the intestinal microbiota. We compared melanoma growth in mice harboring distinct commensal microbiota and observed differences in spontaneous antitumor immunity, which were eliminated upon cohousing or after fecal transfer. Sequencing of the 16S ribosomal RNA identified Bifidobacterium as associated with the antitumor effects. Oral administration of Bifidobacterium alone improved tumor control to the same degree as programmed cell death protein 1 ligand 1 (PD-L1)-specific antibody therapy (checkpoint blockade), and combination treatment nearly abolished tumor outgrowth. Augmented dendritic cell function leading to enhanced CD8(+) T cell priming and accumulation in the tumor microenvironment mediated the effect. Our data suggest that manipulating the microbiota may modulate cancer immunotherapy.
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            Anticancer immunotherapy by CTLA-4 blockade relies on the gut microbiota.

            Antibodies targeting CTLA-4 have been successfully used as cancer immunotherapy. We find that the antitumor effects of CTLA-4 blockade depend on distinct Bacteroides species. In mice and patients, T cell responses specific for B. thetaiotaomicron or B. fragilis were associated with the efficacy of CTLA-4 blockade. Tumors in antibiotic-treated or germ-free mice did not respond to CTLA blockade. This defect was overcome by gavage with B. fragilis, by immunization with B. fragilis polysaccharides, or by adoptive transfer of B. fragilis-specific T cells. Fecal microbial transplantation from humans to mice confirmed that treatment of melanoma patients with antibodies against CTLA-4 favored the outgrowth of B. fragilis with anticancer properties. This study reveals a key role for Bacteroidales in the immunostimulatory effects of CTLA-4 blockade.
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              A Paradigm Shift in Cancer Immunotherapy: From Enhancement to Normalization

              Harnessing an antitumor immune response has been a fundamental strategy in cancer immunotherapy. For over a century, efforts have primarily focused on amplifying immune activation mechanisms that are employed by humans to eliminate invaders such as viruses and bacteria. This "immune enhancement" strategy often results in rare objective responses and frequent immune-related adverse events (irAEs). However, in the last decade, cancer immunotherapies targeting the B7-H1/PD-1 pathway (anti-PD therapy), have achieved higher objective response rates in patients with much fewer irAEs. This more beneficial tumor response-to-toxicity profile stems from distinct mechanisms of action that restore tumor-induced immune deficiency selectively in the tumor microenvironment, here termed "immune normalization," which has led to its FDA approval in more than 10 cancer indications and facilitated its combination with different therapies. In this article, we wish to highlight the principles of immune normalization and learn from it, with the ultimate goal to guide better designs for future cancer immunotherapies.
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                Author and article information

                Contributors
                Journal
                Front Immunol
                Front Immunol
                Front. Immunol.
                Frontiers in Immunology
                Frontiers Media S.A.
                1664-3224
                03 August 2023
                2023
                : 14
                : 1140463
                Affiliations
                [1] 1 Department of Pharmacy, The Second Xiangya Hospital, Central South University , Changsha, China
                [2] 2 Hunan Provincial Engineering Research Centre of Translational Medicine and Innovative Drug , Changsha, China
                [3] 3 Institute of Clinical Pharmacy, Central South University , Changsha, China
                [4] 4 Hunan Key Laboratory of Tumor Models and Individualized Medicine, The Second Xiangya Hospital , Changsha, China
                Author notes

                Edited by: Ouyang Chen, Duke University, United States

                Reviewed by: Tianjiao Geng, The University of Auckland, New Zealand; Guopan Liu, City University of Hong Kong, Hong Kong SAR, China; Wenfei Chen, Sichuan University, China

                *Correspondence: Junyong Wu, wujunyong@ 123456csu.edu.cn ; Daxiong Xiang, xiangdaxiong@ 123456csu.edu.cn
                Article
                10.3389/fimmu.2023.1140463
                10436994
                37600773
                cf1a9b5c-0fbf-4f30-9730-f54dae3bb283
                Copyright © 2023 Zhou, Tang, Xu, Hao, Li, Huang, Xiang and Wu

                This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

                History
                : 09 January 2023
                : 30 March 2023
                Page count
                Figures: 6, Tables: 2, Equations: 0, References: 238, Pages: 23, Words: 9546
                Funding
                Funded by: Hunan Provincial Science and Technology Department , doi 10.13039/501100002767;
                Funded by: Natural Science Foundation of Hunan Province , doi 10.13039/501100004735;
                This research was supported by Hunan Provincial Science and Technology Plan (Grant number 2016TP2002), Natural Science Foundation of Hunan Province (Grant number 2023JJ40860), Natural Science Foundation of Changsha, Hunan Province, China (Grant number kq2208346), China Postdoctoral Science Foundation (Grant number 2023M733962) and Little Lotus' Talent Plan, Hunan Province, China.
                Categories
                Immunology
                Review
                Custom metadata
                Microbial Immunology

                Immunology
                bacteria,immunotherapy,cancer,tumor model,vaccine,colonization
                Immunology
                bacteria, immunotherapy, cancer, tumor model, vaccine, colonization

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