T-cell Localization, Activation, and Clonal Expansion in Human Pancreatic Ductal Adenocarcinoma.
T-cell Localization, Activation, and Clonal Expansion in Human Pancreatic Ductal Adenocarcinoma.
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DOI：
10.1158/2326-6066.cir-16-0322
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发表时间：
2017-11
影响因子：
10.1
通讯作者：
Hingorani SR
中科院分区：
文献类型：
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作者：
Stromnes IM;Hulbert A;Pierce RH;Greenberg PD;Hingorani SR
胰腺导管腺癌（PDA）是一种致命的恶性肿瘤，对大多数疗法（包括免疫检查点阻断）具有耐药性。为了阐明免疫治疗耐药的机制，我们评估了切除的人 PDA 中的免疫参数。我们证明了 T 细胞数量、定位和表型方面存在显着的患者间差异。与基质和肿瘤细胞巢相比，CD8+ T 细胞、Foxp3+ 调节性 T 细胞以及 PD-1+ 和 PD-L1+ 细胞优先富集在大多数肿瘤中发现的三级淋巴结构中。含有更多 CD8+ T 细胞的肿瘤也具有增加的粒细胞、CD163+（M2 免疫抑制表型）巨噬细胞和 FoxP3+ 调节性 T 细胞。 PD-L1 在肿瘤细胞中很少见，但由 CD163+ 巨噬细胞和通常在肿瘤上皮附近聚集在一起的其他基质细胞亚群表达。大多数肿瘤 CD8+ T 细胞不表达暗示近期 T 细胞受体 (TCR) 信号传导的分子。然而，与循环相比，41BB+PD-1+T细胞在肿瘤中仍然显着富集。肿瘤 PD-1+ CD8+ T 细胞通常表达额外的抑制性受体，但主要是 T-bethi 和 Eomeslo，与较少的终末耗尽状态一致。通过深度测序对基因表达和重排 TCR 基因进行的分析表明，大多数患者的肿瘤反应性 T 细胞反应有限。多重免疫组织化学揭示了基于丰度和位置的不同 T 细胞浸润，这可能导致不同的免疫治疗耐药机制。总体而言，数据支持需要诱导内源性或提供工程化的肿瘤特异性 T 细胞反应并同时缓解肿瘤部位的抑制机制的疗法。
Pancreatic ductal adenocarcinoma (PDA) is a lethal malignancy resistant to most therapies, including immune checkpoint blockade. To elucidate mechanisms of immunotherapy resistance, we assessed immune parameters in resected human PDA. We demonstrate significant interpatient variability in T-cell number, localization, and phenotype. CD8+ T cells, Foxp3+ regulatory T cells and PD-1+ and PD-L1+ cells were preferentially enriched in tertiary lymphoid structures that were found in most tumors compared to stroma and tumor cell nests. Tumors containing more CD8+ T cells also had increased granulocytes, CD163+ (M2 immunosuppressive phenotype) macrophages, and FoxP3+ regulatory T cells. PD-L1 was rare on tumor cells, but was expressed by CD163+ macrophages and an additional stromal cell subset commonly found clustered together adjacent to tumor epithelium. The majority of tumoral CD8+ T cells did not express molecules suggestive of recent T-cell receptor (TCR) signaling. However, 41BB+PD-1+ T cells were still significantly enriched in tumors compared to circulation. Tumoral PD-1+ CD8+ T cells commonly expressed additional inhibitory receptors, yet were mostly T-bethi and Eomeslo, consistent with a less terminally exhausted state. Analysis of gene expression and rearranged TCR genes by deep sequencing suggested most patients have a limited tumor-reactive T-cell response. Multiplex immunohistochemistry revealed variable T-cell infiltration based on abundance and location, which may result in different mechanisms of immunotherapy resistance. Overall, the data support the need for therapies that either induce endogenous, or provide engineered, tumor-specific T-cell responses and concurrently relieve suppressive mechanisms operative at the tumor site.