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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

基本信息

批准号：
10304849
负责人：
Aubrey Sinah Smith
金额：
$ 2.9万
依托单位：
MEDICAL UNIVERSITY OF SOUTH CAROLINA
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-12-01 至 2022-04-29
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10304849
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novel overexpression preconditioning programmed cell death protein 1 response side effect stemness tool tumor unpublished works

项目摘要

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。最近，我们发现 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。了解和操纵维持 T 细胞持久性的 TLR 通路将潜在地释放对肿瘤的持久反应。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 或疫苗管理。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）并同时表达 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。我们假设 CD40 CpG 处理后 B 细胞中的信号传导负责 CD8+ TFML 细胞的发育并增强抗肿瘤活性。由 CpG 处理的培养物产生的 CD8+ T 细胞获得了由高值表示的独特表型 IL-2细胞因子受体IL-2R的表达？ CD39 的暗淡表达？我的合作导师马克·鲁宾斯坦博士最近发表的IL-2R的重要性？促进 ACT 模型中 T 细胞的植入。相反，与载体处理的 T 细胞相比，CD39 在 CpG 生成的 T 细胞上仅最低限度表达细胞，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。因此，我寻求研究 CpG 如何诱导这种强效细胞产物的机制以及 IL-2R 的作用？和CD39 实现强大的抗肿瘤反应。总体而言，我假设 TLR9 激动剂 CpG 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。我将在目标 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。这个概念将在目标 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 CPG。此外，这些研究的结果将有助于深入了解具有强免疫学特性的 T 细胞的生成。肿瘤记忆将对癌症患者产生重要的临床意义。总体而言，建议研究预计将证明用 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。