B cells imprint adoptively transferred CD8 + T cells with enhanced tumor immunity.

Autor:	Smith AS; Department of Microbiology and Immunology, Medical University of South Carolina, Charleston, South Carolina, USA aubrey.s.smith@emory.edu chrystal.mary.paulos@emory.edu.; Division of Surgical Oncology, Department of Surgery, Emory University, Atlanta, Georgia, USA.; Department of Microbiology and Immunology, Winship Cancer Institute, Emory University, Atlanta, Georgia, USA., Knochelmann HM; Department of Microbiology and Immunology, Medical University of South Carolina, Charleston, South Carolina, USA.; Division of Surgical Oncology, Department of Surgery, Emory University, Atlanta, Georgia, USA.; Department of Microbiology and Immunology, Winship Cancer Institute, Emory University, Atlanta, Georgia, USA., Wyatt MM; Division of Surgical Oncology, Department of Surgery, Emory University, Atlanta, Georgia, USA.; Department of Microbiology and Immunology, Winship Cancer Institute, Emory University, Atlanta, Georgia, USA., Rangel Rivera GO; Department of Microbiology and Immunology, Medical University of South Carolina, Charleston, South Carolina, USA.; Division of Surgical Oncology, Department of Surgery, Emory University, Atlanta, Georgia, USA.; Department of Microbiology and Immunology, Winship Cancer Institute, Emory University, Atlanta, Georgia, USA., Rivera-Reyes AM; Division of Surgical Oncology, Department of Surgery, Emory University, Atlanta, Georgia, USA.; Department of Microbiology and Immunology, Winship Cancer Institute, Emory University, Atlanta, Georgia, USA., Dwyer CJ; Department of Microbiology and Immunology, Medical University of South Carolina, Charleston, South Carolina, USA., Ware MB; Division of Surgical Oncology, Department of Surgery, Emory University, Atlanta, Georgia, USA.; Department of Microbiology and Immunology, Winship Cancer Institute, Emory University, Atlanta, Georgia, USA., Cole AC; Division of Surgical Oncology, Department of Surgery, Emory University, Atlanta, Georgia, USA.; Department of Microbiology and Immunology, Winship Cancer Institute, Emory University, Atlanta, Georgia, USA., Neskey DM; Department of Otolaryngology-Head and Neck Surgery, Medical University of South Carolina, Charleston, South Carolina, USA.; Department of Cell and Molecular Pharmacology and Developmental Therapeutics, Medical University of South Carolina, Charleston, South Carolina, USA., Rubinstein MP; Division of Medical Oncology, The Ohio State University, Columbus, Ohio, USA., Liu B; Division of Hematology, Department of Internal Medicine, The Ohio State University, Columbus, Ohio, USA., Thaxton JE; Department of Cell Biology & Physiology, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.; Immunotherapy Program, Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA., Bartee E; Department of Internal Medicine, Division of Molecular Medicine, University of New Mexico Health Sciences Center, Albuquerque, New Mexico, USA., Paulos CM; Department of Microbiology and Immunology, Medical University of South Carolina, Charleston, South Carolina, USA aubrey.s.smith@emory.edu chrystal.mary.paulos@emory.edu.; Division of Surgical Oncology, Department of Surgery, Emory University, Atlanta, Georgia, USA.; Department of Microbiology and Immunology, Winship Cancer Institute, Emory University, Atlanta, Georgia, USA.
Jazyk:	angličtina
Zdroj:	Journal for immunotherapy of cancer [J Immunother Cancer] 2022 Jan; Vol. 10 (1).
DOI:	10.1136/jitc-2021-003078
Abstrakt:	Background: Adoptive T cell transfer (ACT) therapy improves outcomes in patients with advanced malignancies, yet many individuals relapse due to the infusion of T cells with poor function or persistence. Toll-like receptor (TLR) agonists can invigorate antitumor T cell responses when administered directly to patients, but these responses often coincide with toxicities. We posited that TLR agonists could be repurposed ex vivo to condition T cells with remarkable potency in vivo, circumventing TLR-related toxicity. Methods: In this study we investigated how tumor-specific murine CD8 + T cells and human tumor infiltrating lymphocytes (TILs) are impacted when expanded ex vivo with the TLR9 agonist CpG. Results: Herein we reveal a new way to reverse the tolerant state of adoptively transferred CD8 + T cells against tumors using TLR-activated B cells. We repurposed the TLR9 agonist, CpG, commonly used in the clinic, to bolster T cell-B cell interactions during expansion for ACT. T cells expanded ex vivo from a CpG-treated culture demonstrated potent antitumor efficacy and prolonged persistence in vivo. This antitumor efficacy was accomplished without in vivo administration of TLR agonists or other adjuvants of high-dose interleukin (IL)-2 or vaccination, which are classically required for effective ACT therapy. CpG-conditioned CD8 + T cells acquired a unique proteomic signature hallmarked by an IL-2Rα high ICOS high CD39 low phenotype and an altered metabolic profile, all reliant on B cells transiently present in the culture. Likewise, human TILs benefitted from expansion with CpG ex vivo, as they also possessed the IL-2Rα high ICOS high CD39 low phenotype. CpG fostered the expansion of potent CD8 + T cells with the signature phenotype and antitumor ability via empowering a direct B-T cell interaction. Isolated B cells also imparted T cells with the CpG-associated phenotype and improved tumor immunity without the aid of additional antigen-presenting cells or other immune cells in the culture. Conclusions: Our results demonstrate a novel way to use TLR agonists to improve immunotherapy and reveal a vital role for B cells in the generation of potent CD8 + T cell-based therapies. Our findings have immediate implications in the clinical treatment of advanced solid tumors. Competing Interests: Competing interests: No, there are no competing interests. (© Author(s) (or their employer(s)) 2022. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)
Databáze:	MEDLINE
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