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

• Type of Material: Article
• Authors: Aubrey S Smith, Medical University of South Carolina; Hannah M Knochelmann, Emory University; Megan M Wyatt, Emory University; Guilermo Rangel O Rivera, Medical University of South Carolina; Amalia M Rivera-Reyes, Emory University; Connor J Dwyer, Medical University of South Carolina; Michael B Ware, Emory University; Anna C Cole, Emory University; David M Neskey, Medical University of South Carolina; Mark P Rubinstein, Ohio State University; Bei Liu, Ohio State University; Jessica E Thaxton, University of North Carolina; Eric Bartee, University of New Mexico; Chrystal Paulos, Emory University
• Language: English
• Date: 2022-01-01
• Publisher: BMJ PUBLISHING GROUP
• Publication Version: Final Published Version
• Copyright Statement: © 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.
• License: Creative Commons Attribution-NonCommercial 4.0 International
• Final Published Version (URL): http://dx.doi.org/10.1136/jitc-2021-003078
• Title of Journal or Parent Work: JOURNAL FOR IMMUNOTHERAPY OF CANCER
• Volume: 10
• Issue: 1
• Grant/Funding Information: This work was supported by NCI F31 CA232646-01A1 and Hollings Cancer Center Graduate Fellowship (ASS), NIDCR K08 DE26542 and SCTR UL1TR001450 (DMN), Hollings Cancer Center Proteomics Pilot Award (ASS and CP), NCI R01 CA175061, R01 CA208514 (CP).
• Keywords: Science & Technology; PEPTIDE; IN-SITU VACCINATION; Life Sciences & Biomedicine; EFFICACY; COMPUTATIONAL PLATFORM; immunotherapy; MEMORY; EXPRESSION; lymphocytes; Oncology; RESPONSES; B-lymphocytes; T-lymphocytes; CPG; tumor-infiltrating; adoptive; IMMUNOTHERAPY; SURVIVAL; Immunology; melanoma
• Research Categories: Health Sciences, Pharmacology; Health Sciences, Oncology

Abstract

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.