Identification of a tumor-reactive T-cell repertoire in the immune infiltrate of patients with resectable pancreatic ductal adenocarcinoma
Identification of a tumor-reactive T-cell repertoire in the immune infiltrate of patients with resectable pancreatic ductal adenocarcinoma
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DOI：
10.1080/2162402x.2016.1240859
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发表时间：
2016-01-01
期刊：
影响因子：
7.2
通讯作者：
Offringa, Rienk
中科院分区：
文献类型：
--
作者：
Poschke, Isabel;Faryna, Marta;Offringa, Rienk
目的：可切除的胰腺导管腺癌（PDA）患者的毁灭性预后提出了迫切需要开发针对播散性肿瘤细胞的治疗策略。到目前为止，T细胞疗法几乎没有在PDA中进行，因为普遍认为它代表了一种免疫原性差的肿瘤。实验设计：我们通过免疫组织化学、流式细胞术、T细胞受体（TCR）深度测序和体外扩增T细胞培养物的功能分析，系统分析了127例可切除PDA患者肿瘤活检组织中的T细胞浸润。平行研究进行肿瘤浸润淋巴细胞（TIL）从44例转移性melanoma.Results：突出的T细胞浸润，以及三级淋巴结构窝藏增殖T细胞，检测到绝大多数的活检从PDA患者。TCR深度测序强化了肿瘤是局部T细胞扩增位点的概念，揭示了肿瘤中的T细胞库由高度频繁的CDR3序列主导，与外周血相比，CDR3序列在肿瘤中富集高达10，000倍。事实上，PDA中的TCR库组成与黑色素瘤相似。此外，在体外扩增的TILs是同样有效的PDA和黑色素瘤，导致T细胞培养显示HLA I类限制性反应对自体tumor cells.Conclusions：肿瘤浸润性T细胞反应在PDA显示惊人的相似性，在黑色素瘤，过继性T细胞治疗具有显着的治疗效果。我们的研究结果表明，T细胞为基础的治疗可用于对抗可切除的PDA患者的疾病复发。
Purpose: The devastating prognosis of patients with resectable pancreatic ductal adenocarcinoma (PDA) presents an urgent need for the development of therapeutic strategies targeting disseminated tumor cells. Until now, T-cell therapy has been scarcely pursued in PDA, due to the prevailing view that it represents a poorly immunogenic tumor. Experimental design: We systematically analyzed T-cell infiltrates in tumor biopsies from 127 patients with resectable PDA by means of immunohistochemistry, flow cytometry, T-cell receptor (TCR) deep-sequencing and functional analysis of in vitro expanded T-cell cultures. Parallel studies were performed on tumor-infiltrating lymphocytes (TIL) from 44 patients with metastatic melanoma.Results: Prominent T-cell infiltrates, as well as tertiary lymphoid structures harboring proliferating T-cells, were detected in the vast majority of biopsies from PDA patients. The notion that the tumor is a site of local T-cell expansion was strengthened by TCR deep-sequencing, revealing that the T-cell repertoire in the tumor is dominated by highly frequent CDR3 sequences that can be up to 10,000-fold enriched in tumor as compared to peripheral blood. In fact, TCR repertoire composition in PDA resembled that in melanoma. Moreover, in vitro expansion of TILs was equally efficient for PDA and melanoma, resulting in T-cell cultures displaying HLA class I-restricted reactivity against autologous tumor cells.Conclusions: The tumor-infiltrating T-cell response in PDA shows striking similarity to that in melanoma, where adoptive T-cell therapy has significant therapeutic impact. Our findings indicate that T-cell-based therapies may be used to counter disease recurrence in patients with resectable PDA.