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novel; overexpression; preconditioning; programmed cell death protein 1; response; side effect; stemness; tool; tumor; unpublished works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 使用肿瘤浸润T淋巴细胞（TIL）的收养细胞转移（ACT）疗法用于癌症患者 无法实现全部电势，这主要是由于耗尽的短寿命CD8+ T细胞的转移 发现TC细胞适应性可以通过用Toll样受体9中的B TIL培养中的B细胞改进来改善。 （TLR）激动剂CPG。 可能对肿瘤的持久响应进行解锁。 为了促进T细胞肿瘤的免疫力。 由CpG处理的培养物产生，能够在体内消除肿瘤，而无需IL-2或 疫苗给药。 蛋白质）和伴随CD8+ T细胞表达CD40L。 CXCR5，ICOS和PD-1表达的卵泡记忆样（TFML）表型。 CPG处理后B细胞中的信号传导负责CD8+ TFML细胞的发展并增强 抗肿瘤活性。 IL-2细胞因子受体IL-2R的表达？ 最近发表了IL-2R的重要性？ 相反，CD39仅在CpG生成的T细胞上最小表达对T型T的T细胞 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。 研究CPG如何诱导这种有效的细胞产物以及IL-2R和CD39的作用的机制 在达到强大的抗肿瘤反应时，我假设TLR9 Angnist CpG在 抗肿瘤T细胞培养，通过B细胞中的CD40信号促进T细胞以TFML表型的印记。 会在AIM 1中检查这个想法。此外，我认为IL-2R和CD39，由TLR9信号成反 负责增加该概念的采用转移CD8+ T细胞的抗逆数特性 在AIM 2中进行分析。发现如何通过CpG激活B细胞以成为有效的抗原呈现 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。 对肿瘤的记忆将对癌症的合理性具有重要的临床意义 漏洞的研究表明，用CpG激活TLR9途径可能会诱导 耐用的免疫力抵抗晚期肿瘤的生长和复发。