Greenberg Steven A
Department of Neurology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA.
Oncotarget. 2025 Jan 20;16:1-8. doi: 10.18632/oncotarget.28679.
Recently, combination checkpoint therapy of cancer has been recognized as producing additive as opposed to synergistic benefit due in part to positively correlated effects. The potential for uncorrelated or negatively correlated therapies to produce true synergistic benefits has been noted. Whereas the inhibitory receptors PD-1, CTLA-4, TIM-3, LAG-3, and TIGIT have been collectively characterized as exhaustion receptors, another inhibitory receptor KLRG1 was historically characterized as a senescent receptor and received relatively little attention as a potential checkpoint inhibitor target. The anti-tumor effects of KLRG1 blockade has relatively recently been demonstrated in preclinical studies. Here, expression of the inhibitory receptors PD-1, CTLA-4, TIM-3, LAG-3, TIGIT, and KLRG1 was studied in publicly available gene expression datasets. Bulk RNA microarray and RNAseq, and single cell RNAseq data from healthy blood and tumor tissue samples were analyzed for Pearson correlation. CD8 T cell differentiation of memory T cells from the TEM to TEMRA states is characterized by PD-1/KLRG1 anti-correlation, with decreased PD-1 expression but increased KLRG1 expression. Single cell RNAseq analysis of tumor infiltrating CD8 T cells shows positive correlation of CTLA-4, TIM-3, LAG-3, TIGIT, GITR, 4-1BB, and OX40 with PD-1 but negative correlation of KLRG1 with PD-1. The anti-correlation of PD-1 and KLRG1 expression in human tumor infiltrating CD8 T cells suggests the potential for combination therapy supra-additive benefits of anti-PD-1 and anti-KLRG1 therapies.
最近,癌症联合检查点疗法被认为产生的是累加效应而非协同效应,部分原因是存在正相关效应。已有人指出,不相关或负相关疗法产生真正协同效益的可能性。虽然抑制性受体PD-1、CTLA-4、TIM-3、LAG-3和TIGIT已被统称为耗竭受体,但另一种抑制性受体KLRG1在历史上被表征为衰老受体,作为潜在的检查点抑制剂靶点受到的关注相对较少。KLRG1阻断的抗肿瘤作用最近在临床前研究中得到了证实。在此,我们在公开的基因表达数据集中研究了抑制性受体PD-1、CTLA-4、TIM-3、LAG-3、TIGIT和KLRG1的表达。对来自健康血液和肿瘤组织样本的批量RNA微阵列、RNA测序以及单细胞RNA测序数据进行了Pearson相关性分析。记忆T细胞从TEM向TEMRA状态的CD8 T细胞分化的特征是PD-1/KLRG1呈反相关,即PD-1表达降低但KLRG1表达增加。对肿瘤浸润性CD8 T细胞的单细胞RNA测序分析显示,CTLA-4、TIM-3、LAG-3、TIGIT、GITR、4-1BB和OX40与PD-1呈正相关,但KLRG1与PD-1呈负相关。人类肿瘤浸润性CD8 T细胞中PD-1和KLRG1表达的反相关表明,抗PD-1和抗KLRG1疗法联合治疗可能产生超累加效益。