Tempus Labs, Inc., Chicago, IL, 60654, USA.
Department of Pathology, University of Chicago, Chicago, IL, 60637, USA.
Nat Commun. 2022 Jul 13;13(1):4053. doi: 10.1038/s41467-022-31769-4.
The efficacy of immune checkpoint blockade (ICB) varies greatly among metastatic non-small cell lung cancer (NSCLC) patients. Loss of heterozygosity at the HLA-I locus (HLA-LOH) has been identified as an important immune escape mechanism. However, despite HLA-I disruptions in their tumor, many patients have durable ICB responses. Here we seek to identify HLA-I-independent features associated with ICB response in NSCLC. We use single-cell profiling to identify tumor-infiltrating, clonally expanded CD4 T cells that express a canonical cytotoxic gene program and NSCLC cells with elevated HLA-II expression. We postulate cytotoxic CD4 T cells mediate anti-tumor activity via HLA-II on tumor cells and augment HLA-I-dependent cytotoxic CD8 T cell interactions to drive ICB response in NSCLC. We show that integrating tumor extrinsic cytotoxic gene expression with tumor mutational burden is associated with longer time to progression in a real-world cohort of 123 NSCLC patients treated with ICB regimens, including those with HLA-LOH.
免疫检查点阻断 (ICB) 在转移性非小细胞肺癌 (NSCLC) 患者中的疗效差异很大。HLA-I 基因座杂合性丢失 (HLA-LOH) 已被确定为一种重要的免疫逃逸机制。然而，尽管肿瘤中存在 HLA-I 破坏，但许多患者仍对 ICB 有持久的反应。在这里，我们试图确定与 NSCLC 中 ICB 反应相关的 HLA-I 独立特征。我们使用单细胞分析来鉴定表达经典细胞毒性基因程序的肿瘤浸润性、克隆扩增的 CD4 T 细胞和 HLA-II 表达上调的 NSCLC 细胞。我们假设细胞毒性 CD4 T 细胞通过肿瘤细胞上的 HLA-II 介导抗肿瘤活性，并增强 HLA-I 依赖性细胞毒性 CD8 T 细胞相互作用，从而推动 NSCLC 中的 ICB 反应。我们表明，将肿瘤外在细胞毒性基因表达与肿瘤突变负担相结合，与接受 ICB 方案治疗的 123 名 NSCLC 患者的真实世界队列中的进展时间延长相关，包括 HLA-LOH 患者。
