Therapeutic modulation of NKG7 in CD8+ T cells increases anti-tumor cytotoxicity and improves response to immune checkpoint inhibitors

Monoclonal antibodies that block PD-1/PD-L1 inhibitory signaling have been successfully used to treat a variety of solid tumor malignancies, but only a subset of patients benefit from this treatment. It remains unclear why the majority of patients fail to respond and what other limiting factors are at play. Here we show that natural killer cell granule protein-7 (NKG7) is critical for the anti-tumor activity of CD8+ T cells and response to anti-PD-1 therapy. We performed single-cell RNA sequencing analysis of peripheral CD8+ T cells from patients treated with anti-PD-1 and found that NKG7 gene expression was decreased in the non-responding patients. Overall design: This study included a total of 8 individual patients; n=4 responders to anti-PD-1 therapy; n=4 non-responders to anti-PD-1 therapy. There are two representative samples from each patient, matching "BL" (baseline) and "PT" (12 weeks post initiation of treatment) timepoints. 8 samples also included VDJ library sequencing, as detailed in sample description below.

阻断PD-1/PD-L1抑制信号通路的单克隆抗体已成功应用于多种实体恶性肿瘤的治疗，但仅部分患者可从该治疗中获益。目前仍不清楚为何多数患者无法对该治疗产生应答，以及尚有哪些其他限制因素在发挥作用。本研究证实，自然杀伤细胞颗粒蛋白7（natural killer cell granule protein-7，NKG7）对于CD8阳性T细胞的抗肿瘤活性以及抗PD-1治疗的应答至关重要。我们对抗PD-1治疗患者的外周血CD8阳性T细胞进行了单细胞RNA测序（single-cell RNA sequencing）分析，发现无应答患者体内的NKG7基因表达水平降低。研究设计：本研究共纳入8名独立患者，其中抗PD-1治疗应答者4例（n=4），无应答者4例（n=4）。每名患者对应2份代表性样本，分别对应"BL"（基线）与"PT"（治疗开始后12周）两个时间节点。另有8份样本进行了VDJ文库测序（VDJ library sequencing），具体细节详见下文样本说明。