CD8+ HELPER-INDEPENDENT T CELLS IN TUMOR THERAPY

描述（由申请人提供）：一项正在进行的NCI试验强调了过继性转移T细胞在黑色素瘤患者中获得临床有意义反应的能力。本项目采用过继免疫治疗（adoptive immunotherapy， AIT）的临床预测小鼠模型来获得仅通过直接临床观察难以获得的机制和翻译指导。我们的实验室最近发现，肿瘤引流淋巴结中存在一个小的低l选择素T细胞亚群，包括具有辅助独立功能的自然致敏抗肿瘤CD8 +效应T细胞（TE）。“辅助独立性”的定义是，当以足够的“独立”剂量给药时，这些CD8 + TE治疗已建立的肿瘤的能力，而不需要同时给药CD4 + TE或辅助治疗，如il -2。我们的目标集中在成功的AIT的三个关键要素：(1)在没有明显的亲和性或亲和力选择力的情况下，TE培养条件可以决定治疗结果；(2)在培养过程中未能清除肿瘤诱导的抑制T细胞（Ts）会破坏AIT的效应期；(3)虽然没有必要使用IL-2等辅助药物，但肺外肿瘤的治愈仍然需要辅助化疗或放疗（RT）。关于成分1，我们正在鉴定培养修饰物，它不仅能过度扩增l -选择素lxw TE，而且还能显著增强其治疗效力。这些修饰不会增加T细胞的亲和性或可检测地调节T细胞受体（TCR）的功能，但确实会导致l -选择素低TE在TCR再接合时耐受凋亡的能力显著增强。这样的修饰进一步使完全有效的低Lselectin TE甚至从临终前小鼠恢复。我们正在描述增强TE抗凋亡的机制及其与增强治疗效力的关系。关于第2部分，我们正在研究乘客t发挥效应阻滞的机制，目的是描述表型或功能差异，以便在过继转移之前定量去除它们。关于成分3，我们已经确定，亚致死照射导致CD34 +细胞外周血动员，共刺激分子表达上调。我们正在描述这些细胞增强肿瘤内抗原呈递的能力，并促进在未接受放疗或化疗的宿主中成功进行AIT。

DESCRIPTION (provided by applicant): An ongoing NCI trial has underscored the capacity of adoptively transferred T cells to achieve clinically meaningful responses in melanoma patients. This project employs clinically predictive mouse models of adoptive immunotherapy (AIT) to obtain mechanistic and translational guidance, which would be difficult to obtain solely through direct clinical observations. Our laboratory recently identified that a small L-selectin low subset of T cells present in tumor-draining lymph nodes includes naturally sensitized antitumor CD8 + effector T cells (TE) with helper-independent function. Helper-independence is defined by the observed ability of these CD8 + TE to cure established tumors when they are administered in sufficient "stand alone" doses, without co-administration of CD4 + TE or adjunct treatments such as rIL-2. Our aims focus on three key elements of successful AIT: (1) TE culture conditions can dictate therapeutic outcome in the absence of apparent avidity or affinity selection forces; (2) failure to purge tumor-induced suppressor T cells (Ts) during culture can subvert the effector phase of AIT; (3) although administration of adjuncts such as IL-2 remains unnecessary, cure of extrapulmonary tumors continues to require adjunct chemotherapy or radiation therapy (RT). In regards to Component 1, we are identifying culture modifications which not only hyperexpand L-selectin lxw TE, but which also strikingly enhance their therapeutic potency. These modifications do not increase T cell avidity or detectably modulate T-cell receptor (TCR) repertoires, but do lead to a markedly enhanced capacity of L-selectin low TE to withstand apoptosis at TCR reengagement. Such modifications have furthermore enabled recovery of fully potent Lselectin low TE even from pre-terminal mice. We are characterizing the mechanism(s) of enhanced TE resistance to apoptosis and its relation to enhanced therapeutic potency. In regards to Component 2, we are investigating the mechanism(s) by which passenger Ts exert effector blockade, with the goal of delineating phenotypic or functional distinctions to enable their quantitative removal prior to adoptive transfer. In regards to Component 3, we have identified that sublethal irradiation results in peripheral blood mobilization of CD34 + cells with up-regulated co-stimulatory molecule expression. We are characterizing the capacity of such cells to enhance intratumoral antigen presentation, and to facilitate successful AIT in hosts, which have not received RT or chemotherapy.