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: 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
• 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novel; overexpression; preconditioning; programmed cell death protein 1; response; side effect; stemness; tool; tumor; unpublished works

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.

项目摘要 癌症患者使用肿瘤浸润T淋巴细胞（TIL）的收养细胞转移（ACT）疗法具有 无法实现其全部潜力，这主要是由于耗尽的短寿命CD8+ T细胞转移了。最近，我们 发现可以通过用Toll样受体9在TIL培养中激活B细胞来提高T细胞适应性9 （TLR）激动剂CpG。理解和操纵维持T细胞持久性的TLR途径 可能解锁对肿瘤的持久反应。此外，关于B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。在此提案中，我们试图阐明T细胞的机制 由CPG处理的培养物产生，能够在不需要IL-2或 疫苗给药。我们的初步数据表明，用CPG处理的B细胞具有明显的CD40（共刺激性 蛋白质）和伴随的CD8+ T细胞表达CD40L。我们发现目前CD8+ T细胞获得T CXCR5，ICOS和PD-1表达表示的Follic存储器样（TFML）表型。我们肯定CD40 CpG处理后B细胞中的信号传导负责CD8+ TFML细胞的发展，并潜在 抗肿瘤活性。由CpG处理的培养物产生的CD8+ T细胞获得了由高高表示的独特表型 IL-2细胞因子受体IL-2R的表达？和CD39的昏暗表达？我的同事马克·鲁宾斯坦博士 最近发布了IL-2R的重要性？在ACT模型中促进T细胞的植入。 相反，与经过处理的t的媒介物相比，CD39仅在CpG生成的T细胞上最小表达 细胞是与病毒和癌症模型中“终端耗尽”的CD8+ T细胞相关的标记。那我想 研究CPG如何诱导该潜在细胞产物和IL-2R的作用的机制？和CD39 在实现强大的抗肿瘤反应时。总体而言，我假设TLR9激动剂CpG激活了B细胞 抗肿瘤T细胞培养，促进T细胞通过B细胞中的CD40信号传导TFML表型印记。我 会在目标1中检查这个想法。此外，我肯定IL-2R？和CD39，由TLR9信号成反比， 负责增加适当转移的CD8+ T细胞的抗肿瘤特性。这个概念会 在AIM 2中进行分析。发现如何通过CpG激活B细胞以成为潜在的抗原呈现 AIM 1中的CD8+ T细胞的细胞将建立一个新的用于用Toll样受体激动剂的癌症治疗的范式 Cpg。此外，这些研究的发现将为具有强烈免疫学的T细胞的产生提供洞察力 对肿瘤的记忆将对癌症患者具有重要的临床意义。总体而言，提议 预计研究将证明，用CpG激活TLR9途径可能会充分诱导 耐用的免疫力抵抗晚期肿瘤的生长和复发。