Cancer Immunology Unit, Research Department of Haematology, University College London Cancer Institute, London, UK.
Department of Medical Oncology, The Royal Marsden NHS Foundation Trust, London, UK.
Nat Med. 2019 Oct;25(10):1549-1559. doi: 10.1038/s41591-019-0592-2. Epub 2019 Oct 7.
Somatic mutations together with immunoediting drive extensive heterogeneity within non-small-cell lung cancer (NSCLC). Herein we examine heterogeneity of the T cell antigen receptor (TCR) repertoire. The number of TCR sequences selectively expanded in tumors varies within and between tumors and correlates with the number of nonsynonymous mutations. Expanded TCRs can be subdivided into TCRs found in all tumor regions (ubiquitous) and those present in a subset of regions (regional). The number of ubiquitous and regional TCRs correlates with the number of ubiquitous and regional nonsynonymous mutations, respectively. Expanded TCRs form part of clusters of TCRs of similar sequence, suggestive of a spatially constrained antigen-driven process. CD8 tumor-infiltrating lymphocytes harboring ubiquitous TCRs display a dysfunctional tissue-resident phenotype. Ubiquitous TCRs are preferentially detected in the blood at the time of tumor resection as compared to routine follow-up. These findings highlight a noninvasive method to identify and track relevant tumor-reactive TCRs for use in adoptive T cell immunotherapy.
体细胞突变与免疫编辑共同驱动非小细胞肺癌（NSCLC）的广泛异质性。在此，我们研究了 T 细胞抗原受体（TCR）库的异质性。肿瘤内和肿瘤间选择性扩增的 TCR 序列数量各不相同，且与非同义突变的数量相关。扩增的 TCR 可细分为存在于所有肿瘤区域的 TCR（普遍存在）和存在于部分区域的 TCR（局部存在）。普遍存在和局部存在的 TCR 数量分别与普遍存在和局部存在的非同义突变数量相关。扩增的 TCR 构成了相似序列 TCR 簇的一部分，提示存在空间受限的抗原驱动过程。携带普遍存在 TCR 的 CD8 肿瘤浸润淋巴细胞表现出功能失调的组织驻留表型。与常规随访相比，在肿瘤切除时，普遍存在的 TCR 更优先在血液中被检测到。这些发现突出了一种非侵入性的方法，可以识别和跟踪相关的肿瘤反应性 TCR，用于过继性 T 细胞免疫治疗。
