A novel T-cell subset able to kill relapsed cancers

一种能够杀死复发癌症的新型 T 细胞亚群

• 批准号: 9291443
• 负责人: Qing Yi
• 金额: $ 36.26万
• 依托单位: CLEVELAND CLINIC LERNER COM-CWRU
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-07-01 至 2021-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9291443
• 关键词: Adoptive Transfer; Advanced Malignant Neoplasm; Antigens; Antitumor Response; Applications Grants; Biological Response Modifiers; CD8-Positive T-Lymphocytes; CD8B1 gene; Cancer Model; Cancer Relapse; Cancer Remission; Cell Therapy; Cells; Clinical; Clinical Research; Colon; Contralateral; Cultured Cells; Cytotoxic T-Lymphocytes; Disease remission; Effector Cell; Epitopes; FDA approved; Foundations; Granzyme; Human; Immune; Immune response; Immune system; Immunotherapy; In Vitro; In complete remission; Interferons; Interleukin-2; Interleukin-9; Leukocytes; Light; Longevity; MC38; Malignant Neoplasms; Malignant neoplasm of prostate; Mediating; Methods; Mus; PPBP gene; Patients; Pharmaceutical Preparations; Primary Neoplasm; Property; Protocols documentation; Recurrence; Recurrent tumor; Relapse; Reporting; Role; SILV gene; Site; Solid; T-Lymphocyte; T-Lymphocyte Subsets; TC1 Cell; Testing; Th1 Cells; Therapeutic; Translating; Tumor Immunity; Variant; antitumor effect; base; cancer immunotherapy; cancer therapy; cytokine; cytotoxic; experience; improved; in vivo; innovation; interest; killings; melanoma; mouse model; neoplastic cell; novel; pre-clinical; pressure; response; tumor; tumor progression

Project Summary The major problem in cancer treatment is that, although patients respond to the initial treatment with cancer remission, the vast majority of the treated patients will have tumor recurrence in the primary and metastatic sites. For patients receiving immunotherapy, the recurring tumor cells frequently become antigen-loss-variants (ALVs) due to pressure and selection by the immune system. ALV outgrowth is an important mechanism by which tumors survive the immune attack and render immunotherapies targeting a single or multiple antigens ineffective. Recently, we discovered that when primed under Th9-polarizing conditions, naïve CD8+ T cells could also differentiate into an IL-9-producing Tc9 subset (Lu et al, Proc Natl Acad Sci USA, 2014). Although less cytolytic in vitro as compared with Tc1 cells, adoptive transfer of tumor-specific Tc9 cells elicits a significantly greater antitumor response against large established melanoma (B16 and B16-OVA) and colon (MC38-gp100) tumors. More importantly, our preliminary studies showed that adoptively transferred tumor (OVA)-specific Tc9 but not Tc1 cells eradicated not only OVA-expressing tumor cells but also large established chimeric tumors containing both OVA-expressing and OVA-negative tumor cells, as well as OVA-negative tumor cells grown on the contralateral flank of mice, indicating that the Tc9 cells could mediate the killing of local bystander and remote ALVs in vivo. Based on these novel findings, we hypothesize that the Tc9 subset may be a superb effector T-cell subset for cancer immunotherapy to eradicate primary and recurrent ALV tumors. Aim 1 will determine whether and how Tc9 cells mediate killing of ALVs via epitope spreading and induction of a host CTL response against other antigens expressed by the tumor cells, and Aim 2 will determine the potential of human tumor-specific Tc9 cells in killing human primary and ALV tumors in vivo. These innovative and mechanistic studies will shed light on the mechanisms underlying Tc9 cell-mediated antitumor immunity and will thus establish a foundation for translating this discovery into more effective immunotherapies using tumor-specific T-cell subsets in human cancers.

项目摘要 癌症治疗的主要问题是，尽管患者对癌症的初始治疗有反应， 在缓解后，绝大多数接受治疗的患者将在原发性和转移性肿瘤中出现肿瘤复发。 网站.对于接受免疫治疗的患者，复发的肿瘤细胞经常成为抗原丢失变体 （ALV）由于压力和免疫系统的选择。ALV的生长是ALV的一个重要机制， 哪些肿瘤在免疫攻击中存活并提供靶向单个或多个抗原的免疫治疗 无效。最近，我们发现当在Th 9极化条件下引发时，幼稚的CD 8 + T细胞 也可以分化成产生IL-9的Tc 9亚群（Lu等人，Proc Natl Acad Sci USA，2014）。虽然 与Tc 1细胞相比，Tc 9细胞在体外的细胞溶解性较低，肿瘤特异性Tc 9细胞的过继转移可以提高Tc 9细胞的细胞溶解性。 对已建立的大型黑素瘤（B16和B16-OVA）和结肠癌的抗肿瘤应答显著更高 （MC 38-gp 100）肿瘤。更重要的是，我们的初步研究表明，过继转移的肿瘤 （OVA）特异性Tc 9而非Tc 1细胞不仅根除了表达OVA的肿瘤细胞，而且还根除了大的已建立的肿瘤细胞。 含有OVA表达和OVA阴性肿瘤细胞以及OVA阴性肿瘤细胞的嵌合肿瘤， 肿瘤细胞生长在小鼠的对侧胁腹，表明Tc 9细胞可以介导肿瘤细胞的杀伤。 本地旁观者和远程ALV体内。基于这些新的发现，我们假设Tc 9亚群 可能是癌症免疫治疗的极好效应T细胞亚群，以根除原发性和复发性ALV 肿瘤的目的1将确定Tc 9细胞是否以及如何通过表位扩散介导ALV的杀伤， 诱导针对肿瘤细胞表达的其它抗原的宿主CTL应答，而Aim 2将 确定人肿瘤特异性Tc 9细胞在体内杀死人原发性肿瘤和ALV肿瘤的潜力。 这些创新性和机制性的研究将阐明Tc 9细胞介导的细胞凋亡的机制。 抗肿瘤免疫，并将因此建立基础，将这一发现转化为更有效的 在人类癌症中使用肿瘤特异性T细胞亚群的免疫疗法。