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.
J Immunother Cancer. 2022 Jan;10(1). doi: 10.1136/jitc-2021-003078.
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.
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.
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-2RαICOSCD39 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-2RαICOSCD39 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.
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.
过继性 T 细胞转移（ACT）疗法改善了晚期恶性肿瘤患者的预后，但由于输注功能差或持续存在的 T 细胞，许多患者复发。当直接给予患者 Toll 样受体（TLR）激动剂时，可激活抗肿瘤 T 细胞反应，但这些反应常伴有毒性。我们假设 TLR 激动剂可以被重新用于体外条件化 T 细胞，从而在体内产生显著的效力，避免 TLR 相关毒性。
在这项研究中，我们研究了 TLR9 激动剂 CpG 体外扩增时对肿瘤特异性鼠 CD8 T 细胞和人肿瘤浸润淋巴细胞（TIL）的影响。
在此，我们揭示了一种使用 TLR 激活的 B 细胞逆转过继转移的 CD8 T 细胞对肿瘤耐受状态的新方法。我们重新利用了 TLR9 激动剂 CpG，该激动剂常用于临床，在 ACT 中扩增时增强 T 细胞-B 细胞相互作用。从 CpG 处理的培养物中体外扩增的 T 细胞表现出强大的抗肿瘤功效，并在体内延长了持久性。这种抗肿瘤功效是在体内不给予 TLR 激动剂或其他高剂量白细胞介素（IL）-2 或疫苗佐剂的情况下实现的，这些佐剂通常是有效 ACT 治疗所必需的。CpG 处理的 CD8 T 细胞获得了独特的蛋白质组学特征，其特征是具有 IL-2RαICOSCD39 表型和改变的代谢谱，所有这些都依赖于培养物中短暂存在的 B 细胞。同样，人 TIL 也受益于 CpG 的体外扩增，因为它们也具有 IL-2RαICOSCD39 表型。CpG 通过增强直接 B-T 细胞相互作用，促进具有特征表型和抗肿瘤能力的强大 CD8 T 细胞的扩增。分离的 B 细胞也赋予 T 细胞 CpG 相关表型，并在培养物中无需额外的抗原呈递细胞或其他免疫细胞的帮助下改善肿瘤免疫。
我们的结果表明了一种使用 TLR 激动剂改善免疫疗法的新方法，并揭示了 B 细胞在产生强大的基于 CD8 T 细胞的疗法中的重要作用。我们的发现立即对晚期实体瘤的临床治疗具有重要意义。
