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Increased spatial coupling of integrin and collagen IV in the immunoresistant clear-cell renal-cell carcinoma tumor microenvironment
Genome Biology ( IF 10.1 ) Pub Date : 2024-12-05 , DOI: 10.1186/s13059-024-03435-z Alex C. Soupir, Mitchell T. Hayes, Taylor C. Peak, Oscar Ospina, Nicholas H. Chakiryan, Anders E. Berglund, Paul A. Stewart, Jonathan Nguyen, Carlos Moran Segura, Natasha L. Francis, Paola M. Ramos Echevarria, Jad Chahoud, Roger Li, Kenneth Y. Tsai, Jodi A. Balasi, Yamila Caraballo Peres, Jasreman Dhillon, Lindsey A. Martinez, Warren E. Gloria, Nathan Schurman, Sean Kim, Mark Gregory, James Mulé, Brooke L. Fridley, Brandon J. Manley
Genome Biology ( IF 10.1 ) Pub Date : 2024-12-05 , DOI: 10.1186/s13059-024-03435-z Alex C. Soupir, Mitchell T. Hayes, Taylor C. Peak, Oscar Ospina, Nicholas H. Chakiryan, Anders E. Berglund, Paul A. Stewart, Jonathan Nguyen, Carlos Moran Segura, Natasha L. Francis, Paola M. Ramos Echevarria, Jad Chahoud, Roger Li, Kenneth Y. Tsai, Jodi A. Balasi, Yamila Caraballo Peres, Jasreman Dhillon, Lindsey A. Martinez, Warren E. Gloria, Nathan Schurman, Sean Kim, Mark Gregory, James Mulé, Brooke L. Fridley, Brandon J. Manley
Immunotherapy has improved survival for patients with advanced clear cell renal cell carcinoma (ccRCC), but resistance to therapy develops in most patients. We use cellular-resolution spatial transcriptomics in patients with immunotherapy naïve and exposed primary ccRCC tumors to better understand immunotherapy resistance. Spatial molecular imaging of tumor and adjacent stroma samples from 21 tumors suggests that viable tumors following immunotherapy harbor more stromal CD8 + T cells and neutrophils than immunotherapy naïve tumors. YES1 is significantly upregulated in immunotherapy exposed tumor cells. Spatial GSEA shows that the epithelial-mesenchymal transition pathway is spatially enriched and the associated ligand-receptor transcript pair COL4A1-ITGAV has significantly higher autocorrelation in the stroma after exposure to immunotherapy. More integrin αV + cells are observed in immunotherapy exposed stroma on multiplex immunofluorescence validation. Compared to other cancers in TCGA, ccRCC tumors have the highest expression of both COL4A1 and ITGAV. Assessing bulk RNA expression and proteomic correlates in CPTAC databases reveals that collagen IV protein is more abundant in advanced stages of disease. Spatial transcriptomics of samples of 3 patient cohorts with cRCC tumors indicates that COL4A1 and ITGAV are more autocorrelated in immunotherapy-exposed stroma compared to immunotherapy-naïve tumors, with high expression among fibroblasts, tumor cells, and endothelium. Further research is needed to understand changes in the ccRCC tumor immune microenvironment and explore potential therapeutic role of integrin after immunotherapy treatment.
中文翻译:
免疫耐药透明细胞肾细胞癌肿瘤微环境中整合素和胶原 IV 的空间偶联增加
免疫疗法提高了晚期透明细胞肾细胞癌 (ccRCC) 患者的生存率,但大多数患者对治疗产生了耐药性。我们在免疫治疗初治和暴露的原发性 ccRCC 肿瘤患者中使用细胞分辨率空间转录组学,以更好地了解免疫治疗耐药性。来自 21 个肿瘤的肿瘤和邻近基质样本的空间分子成像表明,免疫治疗后活的肿瘤比免疫治疗初治肿瘤含有更多的基质 CD8 + T 细胞和中性粒细胞。YES1 在免疫治疗暴露的肿瘤细胞中显著上调。空间 GSEA 显示上皮-间充质转化途径在空间上富集,并且相关的配体-受体转录物对 COL4A1-ITGAV 在暴露于免疫治疗后在基质中具有显着较高的自相关性。在多重免疫荧光验证中,在免疫治疗暴露的基质中观察到更多的整合素 αV + 细胞。与 TCGA 中的其他癌症相比,ccRCC 肿瘤的 COL4A1 和 ITGAV 表达最高。评估 CPTAC 数据库中的大量 RNA 表达和蛋白质组学相关性表明,胶原蛋白 IV 蛋白在疾病晚期更丰富。3 例 cRCC 肿瘤患者队列样本的空间转录组学表明,与未接受过免疫治疗的肿瘤相比,COL4A1 和 ITGAV 在免疫治疗暴露的基质中更具自相关性,在成纤维细胞、肿瘤细胞和内皮细胞中高表达。需要进一步的研究来了解 ccRCC 肿瘤免疫微环境的变化,并探索免疫治疗后整合素的潜在治疗作用。
更新日期:2024-12-05
中文翻译:
免疫耐药透明细胞肾细胞癌肿瘤微环境中整合素和胶原 IV 的空间偶联增加
免疫疗法提高了晚期透明细胞肾细胞癌 (ccRCC) 患者的生存率,但大多数患者对治疗产生了耐药性。我们在免疫治疗初治和暴露的原发性 ccRCC 肿瘤患者中使用细胞分辨率空间转录组学,以更好地了解免疫治疗耐药性。来自 21 个肿瘤的肿瘤和邻近基质样本的空间分子成像表明,免疫治疗后活的肿瘤比免疫治疗初治肿瘤含有更多的基质 CD8 + T 细胞和中性粒细胞。YES1 在免疫治疗暴露的肿瘤细胞中显著上调。空间 GSEA 显示上皮-间充质转化途径在空间上富集,并且相关的配体-受体转录物对 COL4A1-ITGAV 在暴露于免疫治疗后在基质中具有显着较高的自相关性。在多重免疫荧光验证中,在免疫治疗暴露的基质中观察到更多的整合素 αV + 细胞。与 TCGA 中的其他癌症相比,ccRCC 肿瘤的 COL4A1 和 ITGAV 表达最高。评估 CPTAC 数据库中的大量 RNA 表达和蛋白质组学相关性表明,胶原蛋白 IV 蛋白在疾病晚期更丰富。3 例 cRCC 肿瘤患者队列样本的空间转录组学表明,与未接受过免疫治疗的肿瘤相比,COL4A1 和 ITGAV 在免疫治疗暴露的基质中更具自相关性,在成纤维细胞、肿瘤细胞和内皮细胞中高表达。需要进一步的研究来了解 ccRCC 肿瘤免疫微环境的变化,并探索免疫治疗后整合素的潜在治疗作用。