Surgical Services Division, VA Pittsburgh Healthcare System, Pittsburgh, PA 15240, USA.
Department of Cardiothoracic Surgery, University of Pittsburgh School of Medicine, Pittsburgh, PA 15213, USA.
Int J Mol Sci. 2020 Aug 27;21(17):6178. doi: 10.3390/ijms21176178.
While T cell-based cancer immunotherapies have shown great promise, there remains a need to understand how individual metastatic tumor environments impart local T cell dysfunction. At advanced stages, cancers that metastasize to the pleural space can result in a malignant pleural effusion (MPE) that harbors abundant tumor and immune cells, often exceeding 10 leukocytes per liter. Unlike other metastatic sites, MPEs are readily and repeatedly accessible via indwelling catheters, providing an opportunity to study the interface between tumor dynamics and immunity. In the current study, we examined CD8 T cells within MPEs collected from patients with heterogeneous primary tumors and at various stages in treatment to determine (1) if these cells possess anti-tumor activity following removal from the MPE, (2) factors in the MPE that may contribute to their dysfunction, and (3) the phenotypic changes in T cell populations that occur following ex vivo expansion. Co-cultures of CD8 T cells with autologous CD45 tumor containing cells demonstrated cytotoxicity ( = 0.030) and IFNγ production ( = 0.003) that inversely correlated with percent of myeloid derived suppressor cells, lactate, and lactate dehydrogenase (LDH) within the MPE. Ex vivo expansion of CD8 T cells resulted in progressive differentiation marked by distinct populations expressing decreased CD45RA, CCR7, CD127, and increased inhibitory receptors. These findings suggest that MPEs may be a source of tumor-reactive T cells and that the cellular and acellular components suppress optimal function.
虽然基于 T 细胞的癌症免疫疗法显示出巨大的前景,但仍需要了解个体转移性肿瘤环境如何赋予局部 T 细胞功能障碍。在晚期,转移到胸膜腔的癌症可导致恶性胸腔积液(MPE),其中含有丰富的肿瘤和免疫细胞,通常每升超过 10 个白细胞。与其他转移部位不同,MPE 可以通过留置导管轻易且反复地进入,为研究肿瘤动力学和免疫之间的界面提供了机会。在当前的研究中,我们检查了来自具有异质原发性肿瘤和不同治疗阶段的患者的 MPE 中 CD8 T 细胞,以确定:(1)这些细胞从 MPE 中取出后是否具有抗肿瘤活性;(2)MPE 中可能导致其功能障碍的因素;以及(3)在体外扩增后 T 细胞群发生的表型变化。CD8 T 细胞与自体含有 CD45 肿瘤的细胞共培养显示出细胞毒性(= 0.030)和 IFNγ 产生(= 0.003),与 MPE 中的髓源性抑制细胞、乳酸和乳酸脱氢酶(LDH)的百分比呈反比。CD8 T 细胞的体外扩增导致渐进分化,其特征是表达减少的 CD45RA、CCR7、CD127 和增加的抑制性受体的不同群体。这些发现表明,MPE 可能是肿瘤反应性 T 细胞的来源,并且细胞和无细胞成分抑制了最佳功能。