Paper

Recurrent PD-L1 Structural Rearrangements in Natural Killer/T Cell Lymphoma Patients with Complete Response to PD-1 Blockade Therapy

Wan Lu Pang, Teh, Bin Tean, Chan, Thomas Sau-Yan, Nairismagi, Maarja-Liisa, Qing-Qing Cai, Tan, Daryl, Hong, Huangming, Daryl Ming Zhe Cheah, Mohamad Farid, Siok-Bian Ng, Vikneswari Rajasegaran, Wee-Joo Chng, Song, Tammy, Young Ng, Cedric Chuan, Lim, Soon Thye, Lin, Tongyu, Khor, Chiea Chuen, Laurensia, Yurike, Mow, Benjamin, Rotzschke, Olaf, Rozen, Steve, Huang, Dachuan, Burton Kuan Hui Chia, Tan, Jing, Iqbal, Jabed, Goh, Yeow Tee, Hwang, William, Tousseyn, Thomas, Tse, Eric, Chee Leong Cheng, Yok-Lam Kwong, Au-Yeung, Rex, Grigoropoulos, Nicholas Francis, Tang, Tiffany, Jin-Xin, Bei, Jing Quan Lim, Tao, Miriam, Tan, Patrick, Ong, Choon Kiat, Rou-Jun Peng, Li-Mei, Poon, Phipps, Colin, Yuh Shan Lee, Loh, Yvonne, Qi-Chun, Cai

2018

Overview

This study aims to identify recurrent genetic alterations in relapsed or refractory (RR) natural-killer/T-cell lymphoma (NKTL) patients who have achieved complete response (CR) with programmed cell death 1 (PD-1) blockade therapy. Seven of the eleven patients treated with pembrolizumab achieved CR while the remaining four had progressive disease (PD). Using whole genome sequencing (WGS), we found recurrent clonal structural rearrangements (SR) of the PD-L1 gene in four of the seven (57%) CR patients pretreated tumors. These PD-L1 SRs consist of inter-chromosomal translocations, tandem duplication and micro-inversion that disrupted the suppressive function of PD-L1 3'UTR. Interestingly, recurrent JAK3-activating (p.A573V) mutations were also validated in two CR patients tumors that did not harbor the PD-L1 SR. Importantly, these mutations were absent in the four PD cases. With immunohistochemistry (IHC), PD-L1 positivity could not discriminate patients who archived CR (range: 6%-100%) from patients who had PD (range: 35%-90%). PD-1 blockade with pembrolizumab is a potent strategy for RR NKTL patients and genomic screening could potentially accompany PD-L1 IHC positivity to better select patients for anti-PD-1 therapy.

• Publisher: Cold Spring Harbor Laboratory Press,Cold Spring Harbor Laboratory
• Subject: 3' Untranslated regions / Apoptosis / Cell death / Chromosome translocations / Genomes / Genomics / Immunohistochemistry / L1 gene / Lymphocytes T / Lymphoma / Mutation / Natural killer cells / PD-1 protein / PD-L1 protein / Pembrolizumab / T-cell lymphoma / Tumors