CD8+ HELPER-INDEPENDENT T CELLS IN TUMOR THERAPY

描述（由申请人提供）：一项正在进行的NCI试验强调了过继转移T细胞在黑色素瘤患者中实现有临床意义的应答的能力。该项目采用过继免疫治疗（AIT）的临床预测小鼠模型来获得机制和翻译指导，这很难仅通过直接临床观察获得。我们的实验室最近发现，一个小的L-选择素低的T细胞亚群存在于肿瘤引流淋巴结，包括自然致敏的抗肿瘤CD 8+效应T细胞（TE）与辅助非依赖性功能。不依赖于辅助者的定义是，当这些CD 8 + TE以足够的“独立”剂量给药，而不与CD 4 + TE或辅助治疗（如rIL-2）共同给药时，观察到这些CD 8 + TE治愈已建立肿瘤的能力。我们的目标集中在成功的AIT的三个关键要素：（1）TE培养条件可以决定在没有明显的亲合力或亲和力选择力的情况下的治疗结果;（2）在培养过程中未能清除肿瘤诱导的抑制性T细胞（Ts）可以破坏AIT的效应期;（3）尽管仍然不需要施用诸如IL-2的促排剂，但肺外肿瘤的治愈仍然需要辅助化疗或放疗（RT）。关于组分1，我们正在鉴定培养物修饰，其不仅超表达L-选择素lxw TE，而且还显著增强其治疗效力。这些修饰不增加T细胞亲合力或可检测地调节T细胞受体（TCR）库，但确实导致L-选择素低TE在TCR再接合时耐受细胞凋亡的能力显著增强。这样的修饰还使得能够甚至从终末前小鼠中回收完全有效的L选择素低TE。我们正在表征增强的TE对细胞凋亡的抗性的机制及其与增强的治疗效力的关系。关于组分2，我们正在研究乘客Ts发挥效应子阻断作用的机制，目的是描绘表型或功能差异，以使其在过继转移之前能够定量去除。关于组分3，我们已经确定亚致死辐射导致具有上调的共刺激分子表达的CD 34+细胞的外周血动员。我们正在研究这些细胞增强肿瘤内抗原呈递的能力，并促进未接受RT或化疗的宿主成功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.