PBRM1调控染色体开放性逆转免疫抑制微环境促进结直肠癌抗PD1治疗

免疫治疗已成为临床干预结直肠癌（CRC）的重要手段，然而目前其临床应用价值不足。表观遗传调控参与肿瘤免疫原性和免疫微环境的塑造，但在CRC的中仍有待研究。多溴蛋白1-PBRM1，作为染色质重塑复合体SWI/SNF的重要组成，可以调控染色体开放性。前期研究结果表明，CRC中PBRM1突变趋化间质淋巴细胞浸润并促进抗PD1治疗敏感。本研究着眼于PBRM1，通过1、利用CRISPR-Cas9编辑，探究体外CRC细胞中PBRM1的表达和对CRC细胞的调控作用；2、引入人源化小鼠模型，探究体内PBRM1突变诱导免疫细胞趋化；3、ATAC-sequence、RNA-sequence等高通量测序分析PBRM1突变时染色体开放性及转录活跃位点，探究其调控免疫微环境的具体分子机制；4、分析CRC中PBRM1表达与抗PD1治疗敏感性的关联，为临床CRC应用免疫治疗提供科学依据。

Immunotherapy has played an important role on the treatment of CRC, however its clinical application value is insufficient. Recent studies have found that epigenetic regulation is involved in the shaping of tumor immunogenicity and immune microenvironment, but it remains unknown in CRC. Polybromo 1-PBRM1, as an important part of the chromatin remodeling complex SWI/SNF, regulate the chromatin accessibility by using the energy of ATP. The previous studies have shown that PBRM1 mutations in CRC could induce interstitial lymphocyte infiltration and promote tumor sensitivity to anti-PD1 therapy. This study focuses on the correlation between PBRM1 expression of the CRC and the sensitivity of immunotherapy and explores the way to activate immune cells by CRISPR-Cas9. ATAC-sequence and RNA-sequence are used to analyze the chromosomal accessibility and explore the potential signal pathway .This study aims to explore the specific molecular mechanisms that promote the sensitivity of anti-PD1 treatment related with PBRM1 and provides a scientific basis for the application of immunotherapy in colorectal cancer.