ALK fusion variant 3a/b, concomitant mutations, and high PD-L1 expression were associated with unfavorable clinical response to second-generation ALK TKIs...

Objectives: Second-generation anaplastic lymphoma kinase (ALK) tyrosine kinase inhibitors (TKIs) have significantly improved clinical outcomes in patients with advanced ALK-positive non-small cell lung cancer (NSCLC), but clinical responses vary widely. In this study, the impacts of ALK fusion variants, concomitant mutations, and PD-L1 expression on the clinical response were evaluated in patients receiving second-generation ALK TKIs... Conclusion: ALK fusion variant 3a/b, concomitant mutations, and high PD-L1 expression were associated with unfavorable clinical response to second-generation TKIs in ALK-rearranged NSCLC. READ ARTICLE

Lung Cancer DOI:10.1016/j.lungcan.2022.01.006

Authors: Meichen Li, Xue Hou, Jing Chen, Baishen Zhang, Na Wang, Hongyu Han, Likun Chen

A novel model of controlling PD-L1 expression in ALK+ anaplastic large cell lymphoma revealed by CRISPR screening

The success of programmed cell death protein 1 (PD-1)/PD-L1-based immunotherapy highlights the critical role played by PD-L1 in cancer progression and reveals an urgent need to develop new approaches to attenuate PD-L1 function by gaining insight into how its expression is controlled. Anaplastic lymphoma kinase (ALK)-positive anaplastic large-cell lymphoma (ALK+ ALCL) expresses a high level of PD-L1 as a result of the constitutive activation of multiple oncogenic signaling pathways downstream of ALK activity, making it an excellent model in which to define the signaling processes responsible for PD-L1 upregulation in tumor cells. Here, using clustered regularly interspaced short palindromic repeats (CRISPR)/Cas9 library screening, we sought a comprehensive understanding of the molecular effectors required for PD-L1 regulation in ALK+ ALCL. Indeed, we determined that PD-L1 induction is dependent on the nucleophosmin-ALK oncoprotein activation of STAT3, as well as a signalosome containin..... READ ARTICLE

Blood DOI:10.1182/blood.2019001043

Authors: Jing-Ping Zhang, Zhihui Song, Hong-Bo Wang, Lang Lang, Yuan-Zhong Yang, Wenming Xiao, Daniel E. Webster, Wei Wei, Stefan K. Barta, Marshall E. Kadin, Louis M. Staudt, Masao Nakagawa,Yibin Yang

Clinical relevance of PD-L1 expression and CD8+ T cells infiltration in patients with EGFR-mutated and ALK-rearranged lung cancer

EGFR-mutated or ALK-rearranged non-small cell lung cancer (NSCLC) often showed unfavorable clinical benefit to checkpoint inhibitors (CPIs). However, few reports exist with integrated analysis, to interpret the underlying mechanism of poor response to PD-1/PD-L1 inhibitors. We have retrospectively analyzed the tumor microenvironment (TME) based on tumor PD-L1 expression and CD8+ T cells infiltration in patients with EGFR mutations and ALK rearrangements, and the prognostic value of TME subtypes on overall survival (OS).
Patients with EGFR mutations or ALK rearrangements exhibited lower PD-L1 and CD8 co-expression level in TME, which could be responsible for poor response to CPIs. PD-L1 and CD8 co-expression in EGFR-mutated or ALK-rearranged lung cancer is a biomarker for poor prognosis with shorter OS. READ ARTICLE

Lung Cancer DOI:10.1016/j.lungcan.2018.09.010

Authors: Si-yang Liu, Zhong-yi Dong, Si-pei Wu, Zhi Xie, Li-xu Yan, Yu-Fa Li, Hong-hong Yan, Jian Su, Jin-Ji Yang, Qing Zhou, Wen-Zhao Zhong, Hai-Yan Tu, Xue-Ning Yang, Xu-Chao Zhang, Yi-Long Wu