Abstract：
Immune checkpoint blockade (ICB) therapy has improved treatment effects in multiple cancers. Gene mutations in the DNA damage repair pathway (DDR) may cause genomic instability and may relate to the efficacy of ICB. Checkpoint kinase 2 (CHEK2) and polymerase epsilon (POLE) are important genes in the DDR. In this study, we aimed to study the impact of CHEK2 deficiency mutations on the response to ICB. We found that tumors with CHEK2 mutations had a significantly higher tumor mutational burden (TMB) compared to those with CHEK2-WT in a pancancer database. We noted that CHEK2 deficiency mutations potentiated the anti-tumor effect of anti-PD-1 therapy in MC38 and B16 tumor-bearing mice with the decrease of tumor volume and tumor weight after anti-PD-1 treatment. Mechanistically, CHEK2 deficiency tumors were with the increased cytotoxic CD8+ T-cell infiltration, especially cytotoxic CD8+ T cells, and modulated the tumor-immune microenvironment with an upregulated immune inflammatory pathway and antigen presentation pathway after anti-PD-1 treatment. Furthermore, murine models with POLE mutations confirmed that CHEK2 deficiency shaped similar mutational and immune landscapes as POLE mutations after anti-PD-1 treatment. Taken together, our results demonstrated that CHEK2 deficiency mutations may increase the response to ICB (eg. anti-PD-1) by influencing the tumor immune microenvironment. This indicated that CHEK2 deficiency mutations were a potentially predictive biomarker and CHEK2 deficiency may potentiate response to immunotherapy.
摘要：
免疫检查点阻断（ICB）治疗改善了多种癌症的治疗效果。DNA损伤修复途径（DDR）中的基因突变可能导致基因组不稳定，并且可能与ICB的功效有关。检查点激酶2（CHEK2）和聚合酶ε（POLE）是DDR中的重要基因。在这项研究中,我们旨在研究CHEK2缺陷突变对ICB应答的影响.我们发现，与癌症数据库中的CHEK2-WT相比，具有CHEK2突变的肿瘤具有明显更高的肿瘤突变负担（TMB）。我们注意到CHEK2缺陷突变增强了抗PD-1治疗在MC38和B16荷瘤小鼠中的抗肿瘤作用,同时抗PD-1治疗后肿瘤体积和肿瘤重量减小。机械上,CHEK2缺乏症肿瘤有增加的细胞毒性CD8+T细胞浸润，特别是细胞毒性CD8+T细胞，并在抗PD-1治疗后通过上调的免疫炎症途径和抗原呈递途径调节肿瘤免疫微环境。此外，具有POLE突变的小鼠模型证实，CHEK2缺乏在抗PD-1治疗后形成了与POLE突变相似的突变和免疫景观。一起来看,我们的结果表明CHEK2缺陷突变可能会增加对ICB的反应（例如.抗PD-1)通过影响肿瘤免疫微环境。这表明CHEK2缺陷突变是潜在的预测性生物标志物，CHEK2缺陷可能增强对免疫疗法的反应。
