Activating and propagating polyclonal gamma delta T cells with broad specificity for malignancies.
Activating and propagating polyclonal gamma delta T cells with broad specificity for malignancies.
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DOI：
10.1158/1078-0432.ccr-13-3451
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发表时间：
2014-11-15
期刊：
影响因子：
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通讯作者：
Cooper LJ
中科院分区：
文献类型：
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作者：
Deniger DC;Maiti SN;Mi T;Switzer KC;Ramachandran V;Hurton LV;Ang S;Olivares S;Rabinovich BA;Huls MH;Lee DA;Bast RC Jr;Champlin RE;Cooper LJ
激活和扩增表达γδ和γTCR链多克隆库的δT细胞群，用于肿瘤的过继免疫治疗，这一目标尚未实现。以K562肿瘤细胞来源的临床级人工抗原提呈细胞为照射源，激活并扩增临床规模的人γδT细胞。对这些细胞的增殖、TCR表达、记忆表型、细胞因子分泌和肿瘤杀伤进行了测试。γδT细胞的增殖依赖于CD137L的表达以及外源性IL-2和IL-21的加入。培养的γδT细胞表达Vδ1、Vδ2、Vδ3、Vδ5、Vδ7和Vδ8，并带有Vγ2、Vγ3、Vγ7、Vγ8、Vγ9、Vγ10和Vγ11TCR链。与多克隆γT细胞和肿瘤细胞共培养时，Vδ1、Vδ2和Vδ1-δ2neg亚群产生的干扰素-γδ可被PAN-TCRγδ抗体抑制。多克隆γδT细胞可杀死急性和慢性白血病、结肠癌、胰腺癌和卵巢癌细胞，但不能杀死健康的自体或同种异体正常B细胞。封闭抗体证实多克隆γδT细胞通过DNAM 1、NKG2D和TCRγδ的结合而介导肿瘤细胞的杀伤。过继转移表达多克隆和明确VγδTCR链的激活和增殖的δT细胞，给予了卵巢癌移植瘤小鼠的生存等级(多克隆和GT；Vδ1和GT；Vδ1NegVδ2neg和GT；Vδ2)。多克隆γδT细胞可与临床级别的γδT细胞一起激活和增殖，并显示出广泛的抗肿瘤活性，这将有助于在人类实施AAPC T细胞癌的免疫治疗。
To activate and propagate populations of γδT cells expressing polyclonal repertoire of γ and δ TCR chains for adoptive immunotherapy for cancer, which has yet to be achieved. Clinical-grade artificial antigen presenting cells (aAPC) derived from K562 tumor cells were used as irradiated feeders to activate and expand human γδT cells to clinical scale. These cells were tested for proliferation, TCR expression, memory phenotype, cytokine secretion, and tumor killing. γδT cell proliferation was dependent upon CD137L expression on aAPC and addition of exogenous IL-2 and IL-21. Propagated γδT cells were polyclonal as they expressed Vδ1, Vδ2, Vδ3, Vδ5, Vδ7, and Vδ8 with Vγ2, Vγ3, Vγ7, Vγ8, Vγ9, Vγ10, and Vγ11 TCR chains. Interferon-γ production by Vδ1, Vδ2, and Vδ1negVδ2neg subsets was inhibited by pan-TCRγδantibody when added to co-cultures of polyclonal γδT cells and tumor cell lines. Polyclonal γδT cells killed acute and chronic leukemia, colon, pancreatic, and ovarian cancer cell lines, but not healthy autologous or allogeneic normal B cells. Blocking antibodies demonstrated that polyclonal γδT cells mediated tumor cell lysis through combination of DNAM1, NKG2D, and TCRγδ. The adoptive transfer of activated and propagated γδT cells expressing polyclonal versus defined Vδ TCR chains imparted a hierarchy (polyclonal>Vδ1>Vδ1negVδ2neg>Vδ2) of survival of mice with ovarian cancer xenografts. Polyclonal γδT cells can be activated and propagated with clinical-grade aAPC and demonstrate broad anti-tumor activities, which will facilitate the implementation of γδT cell cancer immunotherapies in humans.