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

• Published in: Journal for immunotherapy of cancer Vol. 10; no. 1; p. e003078
• Main Authors: Smith, Aubrey S, Knochelmann, Hannah M, Wyatt, Megan M, Rangel Rivera, Guillermo O, Rivera-Reyes, Amalia M, Dwyer, Connor J, Ware, Michael B, Cole, Anna C, Neskey, David M, Rubinstein, Mark P, Liu, Bei, Thaxton, Jessica E, Bartee, Eric, Paulos, Chrystal M
• Format: Journal Article
• Language: English
• Published: England BMJ Publishing Group Ltd 01.01.2022; BMJ Publishing Group LTD; BMJ Publishing Group
• Series: Original research
• Subjects: adoptive; Animals; Antibodies; Antigens; B-lymphocytes; B-Lymphocytes - immunology; Cancer; Cancer therapies; CD8-Positive T-Lymphocytes - immunology; Cell culture; Clinical trials; Experiments; Female; Humans; Immune Cell Therapies and Immune Cell Engineering; Immunotherapy; Immunotherapy, Adoptive - methods; Laboratory animals; Ligands; Lymphocytes; Male; Melanoma; Melanoma - drug therapy; Mice; Mice, Inbred C57BL; Pathogens; Patients; Peptides; Stem cells; T-lymphocytes; tumor-infiltrating; B-lymphocytes; T-lymphocytes; adoptive; lymphocytes; immunotherapy; melanoma; tumor-infiltrating
• ISSN: 2051-1426; 2051-1426
• DOI: 10.1136/jitc-2021-003078

BackgroundAdoptive 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.MethodsIn 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.ResultsHerein 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-2RαhighICOShighCD39low 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-2RαhighICOShighCD39low 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.ConclusionsOur 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.