结肠癌中同源重组缺陷(HRD)与免疫治疗之间关联的潜在机制尚未被研究。
■从TCGA数据库中获得了456例结肠腺癌（COAD）患者的外显子测序数据和转录组数据。通过GSVA方法计算通路活性评分并进行进一步的生存分析。在外部GEO队列和免疫治疗队列中验证了候选途径的预后价值。
■高HRD患者预后不良，降低肿瘤突变负荷和微卫星不稳定性，更高比例的基因组改变，COAD对免疫疗法的敏感性较低。然后,神经活性配体-受体相互作用通路在高HRD肿瘤中过度激活,在高HRD结肠癌中与免疫抑制相关.此外,该通路与COAD患者的预后和免疫治疗反应相关.此外，该通路中的基因如LTB4R2可用作结肠癌治疗开发的新靶点。
■我们的研究不仅揭示了结肠癌中HRD的潜在机制和神经活性配体-受体相互作用通路的功能，而且为改善结肠癌的免疫治疗反应提供了新的线索。
The potential mechanism underlying the association between Homologous recombination deficiency (HRD) and immunotherapy in colon cancer has not been investigated.
The exon sequencing data and transcriptome data of 456 colon adenocarcinoma (COAD) patients were obtained from the TCGA database. Pathway activity score was calculated by GSVA methods and engaged in further survival analysis. The prognostic value of the candidate pathways was validated in an external GEO cohort and an immunotherapy cohort.
Patients with high HRD were associated with poor prognosis, lower tumor mutation burden and microsatellite instability, higher fraction genome alteration, and less sensitivity to immunotherapy in COAD. And then, the neuroactive ligand-receptor interaction pathway was over-activated in high-HRD tumors and associated with immunosuppression in colon cancer with high HRD. Besides, the pathway was associated with prognosis and immunotherapy response in COAD. Moreover, genes in this pathway such as LTB4R2 can be used as a novel target for therapy development in colon cancer.
Our
study not only revealed the potential mechanism of HRD and the function of the neuroactive ligand-receptor interaction pathway in colon cancer but also provided new clues for the improvement of immunotherapy response in colon cancer.
