Defining a novel role for B cells in imprinting CD8 T cells with potent antitumor activity

定义 B 细胞在印记具有有效抗肿瘤活性的 CD8 T 细胞中的新作用

• 批准号: 10066640
• 负责人: Aubrey Sinah Smith
• 金额: $ 4.55万
• 依托单位: MEDICAL UNIVERSITY OF SOUTH CAROLINA
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-12-01 至 2022-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10066640
• 关键词: Adoptive Cell Transfers; Adoptive Transfer; Agonist; Antigen-Presenting Cells; Antitumor Response; B-Cell Activation; B-Lymphocytes; BLR1 gene; Binding; CD4 Positive T Lymphocytes; CD40 Antigens; CD8-Positive T-Lymphocytes; CD8B1 gene; Cancer Model; Cancer Patient; Cell Culture Techniques; Cells; Chemotherapy and/or radiation; Clinical; Cytokine Receptors; Data; Dendritic Cells; Development; Engraftment; Event; Fostering; Generations; Growth; Immunity; Immunologic Memory; In Vitro; Individual; Infusion procedures; Interleukin 2 Receptor; Interleukin-2; Licensing; Life; Ligands; Light; Malignant Neoplasms; Mediator of activation protein; Membrane Proteins; Memory; Mentors; Methods; Modeling; Mus; PD-1 blockade; Pathway interactions; Patients; Phenotype; Proliferating; Property; Proteins; Publishing; Radiation Injuries; Receptor Signaling; Recurrence; Regulation; Regulatory T-Lymphocyte; Reporting; Research; Role; Shapes; Signal Transduction; Sum; T cell therapy; T-Lymphocyte; TLR9 gene; TNFRSF5 gene; TNFSF5 gene; Testing; Time; Toll-like receptors; Tumor Immunity; Tumor-Infiltrating Lymphocytes; Vaccines; Viral Cancer; Whole-Body Irradiation; Work; cancer therapy; cell type; chemotherapy; cytokine; cytotoxic; exhaust; fitness; genetically modified cells; imprint; improved; in vivo; innovation; insight; macrophage; microbial; microbiome; novel; overexpression; preconditioning; programmed cell death protein 1; response; side effect; stemness; tool; tumor; unpublished works

Project Summary Adoptive cell transfer (ACT) therapies using tumor infiltrating T lymphocytes (TIL) for cancer patients have failed to fulfill their full potential, mostly due to the transfer of exhausted, short-lived CD8+ T cells. Recently, we discovered that T cell fitness can be improved by activating B cells in a TIL culture with the Toll-like receptor 9 (TLR) agonist CpG. Understanding and manipulating the TLR pathways that sustain T cell persistence will potentially unlock durable responses to tumors. Further, there is little research on how B and CD8+ T cells interact to promote T cell tumor immunity. In this proposal we seek to elucidate the mechanism by which T cells generated from a CpG-treated culture, are able to abolish established tumors in vivo without the need of IL-2 or vaccine administration. Our preliminary data shows B cells treated with CpG have overt CD40 (costimulatory protein) and concomitantly CD8+ T cells express CD40L. We found that at this time CD8+ T cells acquire a T follicular memory-like (TFML) phenotype denoted by CXCR5, ICOS, and PD-1 expression. We posit that CD40 signaling in B cells post CpG-treatment is responsible for the development of CD8+ TFML cells and potentiated antitumor activity. CD8+ T cells generated from CpG-treated cultures gain a unique phenotype denoted by high expression of the IL-2 cytokine receptor IL-2R and dim expression of CD39 My co-mentor Dr. Mark Rubinstein recently published the importance of the IL-2R in promoting engraftment of T cells in an ACT model. Conversely, CD39 which is only minimally expressed on CpG-generated T cells compared to vehicle treated T cells, is a marker associated with “terminally exhausted” CD8+ T cells in viral and cancer models. Thus, I seek to study the mechanisms underlying how CpG induces this potent cell product and the roles of IL-2R and CD39 in achieving robust antitumor responses. Overall, I hypothesize that TLR9 agonist CpG activates B cells in an antitumor T cell culture, promoting T cells to be imprinted with a TFML phenotype via CD40 signaling in B cells. I will examine this idea in Aim 1. Moreover, I posit that IL-2R and CD39, inversely regulated by TLR9 signaling, are responsible for augmenting the antitumor properties of adoptively transferred CD8+ T cells. This concept will be analyzed in Aim 2. Uncovering how B cells can be activated by CpG to become potent antigen presenting cells to CD8+ T cells in Aim 1 will establish a new paradigm for cancer therapy with Toll-like receptor agonist CpG. Also, findings from these studies will provide insight into the generation of T cells with strong immunological memory to tumors and will have important clinical implications for patients with cancer. Overall, the proposed research is expected to demonstrate that activation of the TLR9 pathway with CpG may sufficiently induce durable immunity against the growth and recurrence of advanced tumors.

项目概要 使用肿瘤浸润 T 淋巴细胞 (TIL) 治疗癌症患者的过继细胞转移 (ACT) 疗法 未能充分发挥其潜力，主要是由于转移了耗尽的、短命的 CD8+ T 细胞。 发现 T 细胞适应性可以通过使用 Toll 样受体 9 激活 TIL 培养物中的 B 细胞来改善 (TLR) 激动剂 CpG 了解并操纵维持 T 细胞持久性的 TLR 通路。 此外，关于 B 细胞和 CD8+ T 细胞如何相互作用的研究很少。 促进 T 细胞肿瘤免疫 在本提案中，我们试图阐明 T 细胞的机制。 由 CpG 处理的培养物产生，能够消除体内已形成的肿瘤，而不需要 IL-2 或 我们的初步数据显示，用 CpG 处理的 B 细胞具有明显的 CD40（共刺激）。 蛋白），同时 CD8+ T 细胞表达 CD40L 我们发现此时 CD8+ T 细胞获得了 T。 CXCR5、ICOS 和 PD-1 表达表示滤泡记忆样 (TFML) 表型。 CpG 处理后 B 细胞中的信号传导负责 CD8+ TFML 细胞的发育并增强 CpG 处理的培养物产生的 CD8+ T 细胞具有高抗肿瘤活性。 IL-2 细胞因子受体 IL-2Rα 的表达和 CD39 的暗淡表达 我的合作导师 Mark Rubinstein 博士 最近发表了 ACT 模型中 IL-2R 在促进 T 细胞植入方面的重要性。 离线，CD39 与载体处理的 T 细胞相比，仅在 CpG 生成的 T 细胞上最低限度表达 细胞，是与病毒和癌症模型中“最终耗尽”的 CD8+ T 细胞相关的标志物。 研究 CpG 如何诱导这种强效细胞产物的机制以及 IL-2R 和 CD39 的作用 总的来说，我着迷的是 TLR9 激动剂 CpG 可以激活 B 细胞。 抗肿瘤 T 细胞培养，通过 B 细胞中的 CD40 信号传导促进 T 细胞印记 TFML 表型。 将在目标 1 中检验这个想法。此外，我假设 IL-2R 和 CD39 受 TLR9 信号传导反向调节， 负责增强过继转移的 CD8+ T 细胞的抗肿瘤特性。 在目标 2 中进行分析。揭示 B 细胞如何被 CpG 激活，成为有效的抗原呈递 Aim 1 中的 CD8+ T 细胞将为 Toll 样受体激动剂癌症治疗建立新范例 此外，这些研究的结果将有助于深入了解具有强免疫学作用的 T 细胞的生成。 总体而言，该提议对肿瘤患者具有重要的临床意义。 研究预计将证明用 CpG 激活 TLR9 通路可能足以诱导 针对晚期肿瘤的生长和复发的持久免疫力。