T-cell Responses in the Microenvironment of Primary Renal Cell Carcinoma-Implications for Adoptive Cell Therapy
T-cell Responses in the Microenvironment of Primary Renal Cell Carcinoma-Implications for Adoptive Cell Therapy
复制标题
DOI：
10.1158/2326-6066.cir-17-0467
复制
发表时间：
2018-02-01
影响因子：
10.1
通讯作者：
Svane, Inge Marie
中科院分区：
文献类型：
--
作者：
Andersen, Rikke;Westergaard, Marie Christine Wulff;Svane, Inge Marie
大量高效肿瘤反应性T细胞的体外扩增似乎是用自体肿瘤浸润淋巴细胞（TIL）进行有效过继细胞治疗（ACT）的先决条件，如转移性黑色素瘤（MM）中所示。因此，我们试图确定肾细胞癌（RCC）是否浸润有肿瘤反应性T细胞，可以有效地用于过继转移免疫治疗。TIL和自体肿瘤细胞系（TCL）成功地产生了22（92%）和17（77%）的24个连续的原发性RCC标本，并与转移性黑色素瘤产生的比较。在82%的患者（18/22）的CD 8（+）TIL中观察到自体TCLs或新鲜肿瘤细胞的免疫识别。细胞毒性测定证实了RCC-TIL的杀肿瘤能力。RCC-TILs的总体扩展能力与MM-TILs相似。然而，与MM-TIL相比，CD 8（+）T细胞应答的幅度、多功能性和经典扩增方案中的扩增能力较低。与肿瘤反应的RCC-TILs是功能性的，RCC肿瘤的抗原呈递和处理与MM-TILs相似。在CD 4（+）T细胞中观察到直接识别肿瘤与马槟榔诱导的人类白细胞抗原II类过表达（6/12; 50%）。因此，来自原发性RCC标本的TIL可以被分离、扩增，并且可以识别肿瘤。然而，扩增的CD 8（+）RCC-TILs的免疫应答通常弱于MM-TILs，并显示单功能/寡功能模式。选择、富集和扩增肿瘤反应性多功能T细胞的能力在开发用于RCC的具有TIL的有效ACT中可能是至关重要的。总之，从原发性RCC标本中分离的TIL可以识别肿瘤。然而，它们的免疫应答弱于MM-TILs，并显示出单/寡功能模式。选择和扩增多功能T细胞的能力可能会改善RCC的细胞治疗。(C)2018年AACR。
In vitro expansion of large numbers of highly potent tumor-reactive T cells appears a prerequisite for effective adoptive cell therapy (ACT) with autologous tumor-infiltrating lymphocytes (TIL) as shown in metastatic melanoma (MM). We therefore sought to determine whether renal cell carcinomas (RCC) are infiltrated with tumor-reactive T cells that could be efficiently employed for adoptive transfer immunotherapy. TILs and autologous tumor cell lines (TCL) were successfully generated from 22 (92%) and 17 (77%) of 24 consecutive primary RCC specimens and compared with those generated from metastatic melanoma. Immune recognition of autologous TCLs or fresh tumor digests was observed in CD8(+) TILs from 82% of patients (18/22). Cytotoxicity assays confirmed the tumoricidal capacity of RCC-TILs. The overall expansion capacity of RCC-TILs was similar to MM-TILs. However, the magnitude, polyfunctionality, and ability to expand in classical expansion protocols of CD8(+) T-cell responses was lower compared with MM-TILs. The RCC-TILs that did react to the tumor were functional, and antigen presentation and processing of RCC tumors was similar to MM-TILs. Direct recognition of tumors with cytokine-induced overexpression of human leukocyte antigen class II was observed from CD4(+) T cells (6/12; 50%). Thus, TILs from primary RCC specimens could be isolated, expanded, and could recognize tumors. However, immune responses of expanded CD8(+) RCC-TILs were typically weaker than MM-TILs and displayed a mono-/oligofunctional pattern. The ability to select, enrich, and expand tumor-reactive polyfunctional T cells may be critical in developing effective ACT with TILs for RCC. In summary, TILs isolated from primary RCC specimens could recognize tumors. However, their immune responses were weaker than MM-TILs and displayed a mono-/oligofunctional pattern. The ability to select and expand polyfunctional T cells may improve cell therapy for RCC. (C) 2018 AACR.