Smith et al. found that adding CpG in vitro to peptide-stimulated splenocytes from Pmel-1 transgenic mice generated an IL-2Rαhigh ICOShigh CD39low CD8+ T cell product with improved in vivo persistence and efficacy in treating B16F10 tumors. In acquiring this phenotype, T cells did not sense CpG or respond to soluble cues, but required interaction with APCs in the bulk culture. Depletion of B cells, but not DCs, macrophages, CD4+ T cells, or NK cells, prevented this phenotype and in vivo efficacy. Coculture of purified T and B cells with CpG was sufficient to boost T cell persistence and survival of B16F10 tumor-bearing mice treated with adoptive Pmel-1 transfer.
Contributed by Alex Najibi
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-2R_(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-2R_(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.
Author Info: (1) Department of Microbiology and Immunology, Medical University of South Carolina, Charleston, South Carolina, USA aubrey.s.smith@emory.edu chrystal.mary.paulos@emory.edu. Divisi
Author Info: (1) 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. (2) 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. (3) 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. (4) 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. (5) 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. (6) Department of Microbiology and Immunology, Medical University of South Carolina, Charleston, South Carolina, USA. (7) 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. (8) 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. (9) 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. (10) Division of Medical Oncology, The Ohio State University, Columbus, Ohio, USA. (11) Division of Hematology, Department of Internal Medicine, The Ohio State University, Columbus, Ohio, USA. (12) 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. (13) Department of Internal Medicine, Division of Molecular Medicine, University of New Mexico Health Sciences Center, Albuquerque, New Mexico, USA. (14) 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.
