PDF(Pubmed)
Abstract：
Low response rate, treatment relapse, and resistance remain key challenges for cancer treatment with immune checkpoint blockade (ICB). Here we report that loss of specific tumor suppressors (TS) induces an inflammatory response and promotes an immune suppressive tumor microenvironment. Importantly, low expression of these TSs is associated with a higher expression of immune checkpoint inhibitory mediators. Here we identify, by using in vivo CRISPR/Cas9 based loss-of-function screening, that NF1, TSC1, and TGF-β RII as TSs regulating immune composition. Loss of each of these three TSs leads to alterations in chromatin accessibility and enhances IL6-JAK3-STAT3/6 inflammatory pathways. This results in an immune suppressive landscape, characterized by increased numbers of LAG3+ CD8 and CD4 T cells. ICB targeting LAG3 and PD-L1 simultaneously inhibits metastatic progression in preclinical triple negative breast cancer (TNBC) mouse models of NF1-, TSC1- or TGF-β RII- deficient tumors. Our study thus reveals a role of TSs in regulating metastasis via non-cell-autonomous modulation of the immune compartment and provides proof-of-principle for ICB targeting LAG3 for patients with NF1-, TSC1- or TGF-β RII-inactivated cancers.
摘要：
低反应率，治疗复发，耐药性仍然是免疫检查点阻断（ICB）治疗癌症的关键挑战。在这里，我们报道了特异性肿瘤抑制因子（TS）的缺失会诱导炎症反应并促进免疫抑制性肿瘤微环境。重要的是,这些TS的低表达与免疫检查点抑制介质的高表达相关。在这里，我们确定，通过使用基于体内CRISPR/Cas9的功能丧失筛选，NF1、TSC1和TGF-βRII作为TS调节免疫组成。这三个TS中的每一个的缺失导致染色质可及性的改变并增强IL6-JAK3-STAT3/6炎症途径。这导致免疫抑制的景观，以LAG3+CD8和CD4T细胞数量增加为特征。ICB靶向LAG3和PD-L1同时抑制NF1-，临床前三阴性乳腺癌（TNBC）小鼠模型的转移进展。TSC1-或TGF-βRII缺陷型肿瘤。因此，我们的研究揭示了TS通过免疫区室的非细胞自主调节在调节转移中的作用，并为针对NF1-，TSC1或TGF-βRII灭活的癌症。
