Department of Radiation Oncology, Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University, Guangzhou, Guangdong, 510060, China.
The Cancer Hospital of the University of Chinese Academy of Sciences (Zhejiang Cancer Hospital), Hangzhou, Zhejiang, 310022, China.
Nat Commun. 2021 Nov 17;12(1):6655. doi: 10.1038/s41467-021-26821-8.
Small-cell lung cancer (SCLC) is speculated to harbor complex genomic intratumor heterogeneity (ITH) associated with high recurrence rate and suboptimal response to immunotherapy. Here, using multi-region whole exome/T cell receptor (TCR) sequencing as well as immunohistochemistry, we reveal a rather homogeneous mutational landscape but extremely cold and heterogeneous TCR repertoire in limited-stage SCLC tumors (LS-SCLCs). Compared to localized non-small cell lung cancers, LS-SCLCs have similar predicted neoantigen burden and genomic ITH, but significantly colder and more heterogeneous TCR repertoire associated with higher chromosomal copy number aberration (CNA) burden. Furthermore, copy number loss of IFN-γ pathway genes is frequently observed and positively correlates with CNA burden. Higher mutational burden, higher T cell infiltration and positive PD-L1 expression are associated with longer overall survival (OS), while higher CNA burden is associated with shorter OS in patients with LS-SCLC.
小细胞肺癌（SCLC）被认为具有与高复发率和对免疫疗法反应不佳相关的复杂肿瘤内基因组异质性（ITH）。在这里，我们使用多区域全外显子/T 细胞受体（TCR）测序和免疫组织化学，揭示了局限性 SCLC 肿瘤（LS-SCLC）中相对同质的突变景观，但 TCR 库却非常冷且异质。与局限性非小细胞肺癌相比，LS-SCLCs 具有相似的预测新抗原负担和基因组 ITH，但 TCR 库明显更冷且更异质，与更高的染色体拷贝数异常（CNA）负担相关。此外，IFN-γ 通路基因的拷贝数丢失经常观察到，并与 CNA 负担呈正相关。较高的突变负担、较高的 T 细胞浸润和 PD-L1 表达阳性与 LS-SCLC 患者的总生存期（OS）延长相关，而较高的 CNA 负担与 OS 缩短相关。
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