Therapeutics Discovery Division, The University of Texas MD Anderson Cancer Center, Houston, USA.
Department of Systems Biology, The University of Texas MD Anderson Cancer Center, Houston, USA.
Ann Oncol. 2022 Jan;33(1):42-56. doi: 10.1016/j.annonc.2021.09.021. Epub 2021 Oct 13.
BACKGROUND: Despite the importance of tumor-infiltrating T lymphocytes (TILs) in cancer biology, the relationship between TIL phenotypes and their prognostic relevance for localized non-small-cell lung cancer (NSCLC) has not been well established. PATIENTS AND METHODS: Fresh tumor and normal adjacent tissue was prospectively collected from 150 patients with localized NSCLC. Tissue was comprehensively characterized by high-dimensional flow cytometry of TILs integrated with immunogenomic data from multiplex immunofluorescence, T-cell receptor sequencing, exome sequencing, RNA sequencing, targeted proteomics, and clinicopathologic features. RESULTS: While neither the magnitude of TIL infiltration nor specific TIL subsets were significantly prognostic alone, the integration of high-dimensional flow cytometry data identified two major immunotypes (IM1 and IM2) that were predictive of recurrence-free survival independent of clinical characteristics. IM2 was associated with poor prognosis and characterized by the presence of proliferating TILs expressing cluster of differentiation 103, programmed cell death protein 1, T-cell immunoglobulin and mucin-domain containing protein 3, and inducible T-cell costimulator. Conversely, IM1 was associated with good prognosis and differentiated by an abundance of CD8 T cells expressing cytolytic enzymes, CD4 T cells lacking the expression of inhibitory receptors, and increased levels of B-cell infiltrates and tertiary lymphoid structures. While increased B-cell infiltration was associated with good prognosis, the best prognosis was observed in patients with tumors exhibiting high levels of both B cells and T cells. These findings were validated in patient tumors from The Cancer Genome Atlas. CONCLUSIONS: Our study suggests that although the number of infiltrating T cells is not associated with patient survival, the nature of the infiltrating T cells, resolved in distinct TIL immunotypes, is prognostically relevant in NSCLC and may inform therapeutic approaches to clinical care.
背景:尽管肿瘤浸润性 T 淋巴细胞(TIL)在癌症生物学中具有重要意义,但 TIL 表型与局部非小细胞肺癌(NSCLC)的预后相关性尚未得到充分确立。
患者和方法:前瞻性收集了 150 例局部 NSCLC 患者的新鲜肿瘤和正常相邻组织。通过高维流式细胞术对 TIL 进行全面表征,整合了来自多重免疫荧光、T 细胞受体测序、外显子组测序、RNA 测序、靶向蛋白质组学和临床病理特征的免疫基因组学数据。
结果:虽然 TIL 浸润的程度或特定 TIL 亚群本身并没有显著的预后意义,但高维流式细胞术数据的整合确定了两种主要的免疫型(IM1 和 IM2),它们独立于临床特征预测无复发生存。IM2 与预后不良相关,其特征是表达分化簇 103、程序性细胞死亡蛋白 1、T 细胞免疫球蛋白和粘蛋白结构域包含蛋白 3 和诱导性 T 细胞共刺激物的增殖性 TIL。相反,IM1 与良好的预后相关,其特征是表达细胞毒性酶的 CD8 T 细胞丰富、缺乏抑制性受体表达的 CD4 T 细胞和增加的 B 细胞浸润和三级淋巴结构。虽然增加的 B 细胞浸润与良好的预后相关,但在肿瘤中同时具有高水平 B 细胞和 T 细胞的患者预后最佳。这些发现在癌症基因组图谱中的患者肿瘤中得到了验证。
结论:我们的研究表明,尽管浸润 T 细胞的数量与患者的生存无关,但浸润 T 细胞的性质,在不同的 TIL 免疫型中得到解决,与 NSCLC 的预后相关,并可能为临床治疗提供治疗方法。
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