Xiao Yinbo, Wang Hao, Lu Junliang, Pang Junyi, Liu Shiyi, Zhou Yang, Shi Xiaohua, Liang Zhiyong
Department of Pathology, Molecular Pathology Research Center, Peking Union Medical College Hospital, Chinese Academy of Medical Science and Peking Union Medical College, Beijing, China.
Transl Lung Cancer Res. 2024 Dec 31;13(12):3538-3554. doi: 10.21037/tlcr-24-682. Epub 2024 Dec 27.
The tumor immune microenvironment of anaplastic lymphoma kinase (ALK)-rearranged lung adenocarcinoma (LUAD) stratified by ALK fusion variants is poorly pictured. Hence, in this study, we aim to explore the immune heterogeneity of ALK LUAD across different ALK fusion variants and further investigate their significance on clinical prognosis.
A retrospective analysis was conducted on ALK LUAD patients (N=68). DNA and RNA-based next-generation sequencing (NGS) was performed to clarify the specific ALK fusion variants. Clinical and pathological characteristics were compared between long and short ALK variants. To research the immune heterogeneity, multi-fluorescence was carried out to explore the differences in immune properties, such as tumor-infiltrating lymphocyte (TIL) number, TIL subset, and tertiary lymphoid structures (TLS) development, between long and short ALK variants. Furthermore, the prognostic value of these characteristics was analyzed. Finally, the expression of lymphocyte-activation gene-3 (LAG3), one novel immune therapy target, was assessed across ALK LUAD.
LUAD patients with short ALK fusion variant-driven tumors exhibited higher American Joint Committee on Cancer (AJCC) stage as well as larger tumor size than those with long ALK fusion variant-driven tumors. Compared to long ALK fusion variants, there were more TILs, especially natural killer (NK) cells, within short ALK variants. However, fewer TLS were established in cancers harboring short ALK variants than those with long ALK variants. In advanced-stage LUAD patients with ALK fusion, short ALK variants, hot immune status, and high-level NK cells were identified to be adverse prognostic factors, while high-level B cells, as well as the development of TLS, served as positive prognostic factors. As for LAG3 expression, LAG3 immune cells were more enriched in short ALK variants than in long ALK variants.
LUAD patients with short ALK fusion variant-driven tumors exhibited worse prognosis than those with long ALK fusion variant-driven tumors. The tumor immune microenvironments are heterogeneous across different ALK fusion variants with short variants characterized by higher levels of TIL, especially NK cells, but by less TLS development than long variants ALK LUAD, which disfavor disease outcomes.
间变性淋巴瘤激酶（ALK）重排肺腺癌（LUAD）的肿瘤免疫微环境按ALK融合变体分层的情况描述不足。因此，在本研究中，我们旨在探讨不同ALK融合变体的ALK LUAD的免疫异质性，并进一步研究它们对临床预后的意义。
对ALK LUAD患者（N = 68）进行回顾性分析。进行基于DNA和RNA的下一代测序（NGS）以明确特定的ALK融合变体。比较长、短ALK变体之间的临床和病理特征。为研究免疫异质性，进行多荧光检测以探讨长、短ALK变体之间在免疫特性方面的差异，如肿瘤浸润淋巴细胞（TIL）数量、TIL亚群和三级淋巴结构（TLS）发育情况。此外，分析这些特征的预后价值。最后，评估一种新型免疫治疗靶点淋巴细胞激活基因3（LAG3）在ALK LUAD中的表达。
与长ALK融合变体驱动的肿瘤患者相比，短ALK融合变体驱动的LUAD患者表现出更高的美国癌症联合委员会（AJCC）分期以及更大的肿瘤大小。与长ALK融合变体相比，短ALK变体中有更多的TIL，尤其是自然杀伤（NK）细胞。然而，与长ALK变体的癌症相比，携带短ALK变体的癌症中建立的TLS较少。在晚期ALK融合的LUAD患者中，短ALK变体、热免疫状态和高水平NK细胞被确定为不良预后因素，而高水平B细胞以及TLS的发育则作为阳性预后因素。至于LAG3表达，LAG3免疫细胞在短ALK变体中比在长ALK变体中更富集。
短ALK融合变体驱动的肿瘤的LUAD患者预后比长ALK融合变体驱动的肿瘤患者更差。不同ALK融合变体的肿瘤免疫微环境是异质性的，短变体的特征是TIL水平较高，尤其是NK细胞，但与长变体ALK LUAD相比，TLS发育较少，这不利于疾病结局。
