Microbial metabolite-guided CAR T cell engineering enhances anti-tumor immunity via epigenetic-metabolic crosstalk.

Autor:	Staudt S; Lehrstuhl für Zelluläre Immuntherapie, Medizinische Klinik und Poliklinik II, Universitätsklinikum Würzburg, Würzburg, Germany., Nikolka F; Department of Bioinformatics and Biochemistry, Braunschweig Integrated Centre of Systems Biology (BRICS), Technische Universität Braunschweig, Braunschweig, Germany., Perl M; University Hospital Regensburg, Department of Internal Medicine III, Hematology & Internal Oncology, Regensburg, Germany., Franz J; Lehrstuhl für Zelluläre Immuntherapie, Medizinische Klinik und Poliklinik II, Universitätsklinikum Würzburg, Würzburg, Germany., Leblay N; Arnie Charbonneau Cancer Institute, University of Calgary, Calgary, Alberta, Canada., Yuan XK; Precision Oncology Hub, Arnie Charbonneau Cancer Institute, University of Calgary, Calgary, Alberta, Canada., Warmuth L; Institute for Medical Microbiology, Immunology and Hygiene, Technical University of Munich, Munich, Germany., Fantes MA; University Hospital Regensburg, Department of Internal Medicine III, Hematology & Internal Oncology, Regensburg, Germany., Skorupskaitė A; Life Sciences Center - European Molecular Biology Laboratory (LSC-EMBL) Partnership for Genome Editing Technologies, Vilnius University - Life Sciences Center, Vilnius University, Vilnius, Lithuania., Fei T; Department of Epidemiology and Biostatistics, Memorial Sloan Kettering Cancer Center, New York, New York., Bromberg M; Department of Epidemiology and Biostatistics, Memorial Sloan Kettering Cancer Center, New York, New York., Martin-Uriz PS; Hemato-Oncology Program, Cima Universidad de Navarra, Centro de Investigacion Biomedica en Red de Cancer (CIBERONC), Cancer Center Clinica Universidad de Navarra (CCUN), IdiSNA, Pamplona, Spain., Rodriguez-Madoz JR; Hemato-Oncology Program, Cima Universidad de Navarra, Centro de Investigacion Biomedica en Red de Cancer (CIBERONC), Cancer Center Clinica Universidad de Navarra (CCUN), IdiSNA, Pamplona, Spain., Ziegler-Martin K; Lehrstuhl für Zelluläre Immuntherapie, Medizinische Klinik und Poliklinik II, Universitätsklinikum Würzburg, Würzburg, Germany., Gholam NA; Lehrstuhl für Zelluläre Immuntherapie, Medizinische Klinik und Poliklinik II, Universitätsklinikum Würzburg, Würzburg, Germany., Benz P; Lehrstuhl für Zelluläre Immuntherapie, Medizinische Klinik und Poliklinik II, Universitätsklinikum Würzburg, Würzburg, Germany., Tran PH; Medical University of Vienna, Center for Pathophysiology, Infectiology and Immunology, Institute of Immunology, Vienna, Austria., Freitag F; Lehrstuhl für Zelluläre Immuntherapie, Medizinische Klinik und Poliklinik II, Universitätsklinikum Würzburg, Würzburg, Germany., Riester Z; Lehrstuhl für Zelluläre Immuntherapie, Medizinische Klinik und Poliklinik II, Universitätsklinikum Würzburg, Würzburg, Germany.; Mildred Scheel Early Career Center, University Hospital of Würzburg, Würzburg, Germany., Stein-Thoeringer C; Innere Medizin I, Universitätsklinikum Tübingen & M3 Research Center, Universitätsklinikum Tübingen., Schmitt M; Department of Hematology, Oncology and Rheumatology, University Clinic Heidelberg, Heidelberg, Germany., Kleigrewe K; Bavarian Center for Biomolecular Mass Spectrometry (BayBioMS), Technical University of Munich, Freising, Germany., Weber J; Lehrstuhl für Zelluläre Immuntherapie, Medizinische Klinik und Poliklinik II, Universitätsklinikum Würzburg, Würzburg, Germany., Mangold K; Lehrstuhl für Zelluläre Immuntherapie, Medizinische Klinik und Poliklinik II, Universitätsklinikum Würzburg, Würzburg, Germany.; Institute for Medical Microbiology and Hygiene, Philipps-University Marburg, Marburg, Germany., Einsele H; Medizinische Klinik und Poliklinik II, Universitätsklinikum Würzburg, Würzburg, Germany., Prosper F; Hematology and Cell Therapy Department, Clinica Universidad de Navarra (CUN), Hemato-Oncology Program, Cima Universidad de Navarra. Centro de Investigacion Biomedica en Red de Cancer (CIBERONC), Cancer Center Clinica Universidad de Navarra (CCUN), IdiSNA, Pamplona, Spain., Ellmeier W; Medical University of Vienna, Center for Pathophysiology, Infectiology and Immunology, Institute of Immunology, Vienna, Austria., Busch D; Institute for Medical Microbiology, Immunology and Hygiene, Technical University of Munich, Munich, Germany., Visekruna A; Institute for Medical Microbiology and Hygiene, Philipps-University Marburg, Marburg, Germany., Slingerland J; City of Hope Comprehensive Cancer Center, Duarte, CA., Shouval R; Adult Bone Marrow Transplantation Service and Cellular Therapy Service, Memorial Sloan Kettering Cancer Center, New York, New York.; Weill Cornell Medical College, New York, New York., Hiller K; Department of Bioinformatics and Biochemistry, Braunschweig Integrated Centre of Systems Biology (BRICS), Technische Universität Braunschweig, Braunschweig, Germany., van den Brink M; City of Hope Comprehensive Cancer Center, Duarte, CA., Pausch P; Life Sciences Center - European Molecular Biology Laboratory (LSC-EMBL) Partnership for Genome Editing Technologies, Vilnius University - Life Sciences Center, Vilnius University, Vilnius, Lithuania., Neri P; Arnie Charbonneau Cancer Institute, University of Calgary, Calgary, Alberta, Canada., Hudecek M; Lehrstuhl für Zelluläre Immuntherapie, Medizinische Klinik und Poliklinik II, Universitätsklinikum Würzburg, Würzburg, Germany.; Bavarian Cancer Research Center (BZKF), Regensburg & Würzburg, Germany., Poeck H; University Hospital Regensburg, Department of Internal Medicine III, Hematology & Internal Oncology, Regensburg, Germany.; Bavarian Cancer Research Center (BZKF), Regensburg & Würzburg, Germany.; Leibniz Institute for Immunotherapy (LIT), Regensburg, Germany., Luu M; Lehrstuhl für Zelluläre Immuntherapie, Medizinische Klinik und Poliklinik II, Universitätsklinikum Würzburg, Würzburg, Germany.; Leibniz Institute for Immunotherapy (LIT), Regensburg, Germany.
Jazyk:	angličtina
Zdroj:	BioRxiv : the preprint server for biology [bioRxiv] 2024 Sep 13. Date of Electronic Publication: 2024 Sep 13.
DOI:	10.1101/2024.08.19.608538
Abstrakt:	Emerging data have highlighted a correlation between microbiome composition and cancer immunotherapy outcome. While commensal bacteria and their metabolites are known to modulate the host environment, contradictory effects and a lack of mechanistic understanding impede the translation of microbiome-based therapies into the clinic. In this study, we demonstrate that abundance of the commensal metabolite pentanoate is predictive for survival of chimeric antigen receptor (CAR) T cell patients in two independent cohorts. Its implementation in the CAR T cell manufacturing workflow overcomes solid tumor microenvironments in immunocompetent cancer models by hijacking the epigenetic-metabolic crosstalk, reducing exhaustion and promoting naive-like differentiation. While synergy of clinically relevant drugs mimicked the phenotype of pentanoate-engineered CAR T cells in vitro , in vivo challenge showed inferior tumor control. Metabolic tracing of 13 C-pentanoate revealed citrate generation in the TCA cycle via the acetyl- and succinyl-CoA entry points as a unique feature of the C5 aliphatic chain. Inhibition of the ATP-citrate lyase, which links metabolic output and histone acetylation, led to accumulation of pentanoate-derived citrate from the succinyl-CoA route and decreased functionality of SCFA-engineered CAR T cells. Our data demonstrate that microbial metabolites are incorporated as epigenetic imprints and implementation into CAR T cell production might serve as embodiment of the microbiome-host axis benefits for clinical applications. Competing Interests: ML, MH and AV are listed as inventors on patent application WO2021/058811A1. MH is listed as an inventor on patent applications and granted patents related to CAR-T technologies that have been filed by the Fred Hutchinson Cancer Research Center, Seattle, WA and by the University of Würzburg, Würzburg, Germany. MH is a co-founder and equity owner of T-CURX GmbH, Würzburg, Germany. MH received honoraria from Celgene/BMS, Janssen, Kite/Gilead. MvdB has received research support and stock options from Seres Therapeutics and stock options from Notch Therapeutics and Pluto Therapeutics; he has received royalties from Wolters Kluwer; has consulted, received honorarium from or participated in advisory boards for Seres Therapeutics, Rheos Medicines, Ceramedix, Pluto Therapeutics, Thymofox, Garuda, Novartis (Spouse), Synthekine (Spouse), Beigene (Spouse), Kite (Spouse); he has IP Licensing with Seres Therapeutics and Juno Therapeutics; and holds a fiduciary role on the Foundation Board of DKMS (a nonprofit organization). PN received honoraria from BMS, Janssen, Sanofi and Pfizer as a consultant/advisory board member. MAF received honoraria from Novartis and Sanofi and travel grants from Sanofi. HP is a consultant for Gilead, Abbvie, Pfizer, Novartis, Servier, and Bristol Myers-Squibb. The remaining authors declare no financial conflict of interest.
Databáze:	MEDLINE
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