{"title":"原发性透明细胞肾细胞癌和匹配转移组织中免疫表型与基因型的关联。","authors":"","doi":"10.1016/j.modpat.2024.100558","DOIUrl":null,"url":null,"abstract":"<div><p>Adjuvant immunotherapy has been recently recommended for patients with metastatic clear cell renal cell carcinoma (ccRCC), but there are no tissue biomarkers to predict treatment response in ccRCC. Potential predictive biomarkers are mainly assessed in primary tumor tissue, whereas metastases (METs) remain understudied. To explore potential differences between genomic alterations and immune phenotypes in primary tumors and their matched METs, we analyzed primary tumors (PTs) of 47 ccRCC patients and their matched distant METs by comprehensive targeted parallel sequencing, whole-genome copy number variation analysis, determination of microsatellite instability, and tumor mutational burden. We quantified the spatial distribution of tumor-infiltrating CD8<sup>+</sup> T cells and coexpression of the T-cell-exhaustion marker thymocyte selection-associated high mobility group box (TOX) by digital immunoprofiling and quantified tertiary lymphoid structures. Most METs were pathologically “cold.” Inflamed, pathologically “hot” PTs were associated with decreased disease-free survival, worst for patients with high levels of CD8<sup>+</sup>TOX<sup>+</sup> T cells. Interestingly, inflamed METs showed a relative increase in exhausted CD8<sup>+</sup>TOX<sup>+</sup> T cells and increased accumulative size of tertiary lymphoid structures compared with PTs. Integrative analysis of molecular and immune phenotypes revealed <em>BAP1</em> and <em>CDKN2A/B</em> deficiency to be associated with an inflamed immune phenotype. Our results highlight the distinct spatial distribution and differentiation of CD8+ T cells at metastatic sites, and the association of an inflamed microenvironment with specific genomic alterations.</p></div>","PeriodicalId":18706,"journal":{"name":"Modern Pathology","volume":null,"pages":null},"PeriodicalIF":7.1000,"publicationDate":"2024-07-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S0893395224001388/pdfft?md5=64710c524cf3d80798aa4ff621a2d88a&pid=1-s2.0-S0893395224001388-main.pdf","citationCount":"0","resultStr":"{\"title\":\"Immune Phenotype-Genotype Associations in Primary Clear Cell Renal Cell Carcinoma and Matched Metastatic Tissue\",\"authors\":\"\",\"doi\":\"10.1016/j.modpat.2024.100558\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<div><p>Adjuvant immunotherapy has been recently recommended for patients with metastatic clear cell renal cell carcinoma (ccRCC), but there are no tissue biomarkers to predict treatment response in ccRCC. Potential predictive biomarkers are mainly assessed in primary tumor tissue, whereas metastases (METs) remain understudied. To explore potential differences between genomic alterations and immune phenotypes in primary tumors and their matched METs, we analyzed primary tumors (PTs) of 47 ccRCC patients and their matched distant METs by comprehensive targeted parallel sequencing, whole-genome copy number variation analysis, determination of microsatellite instability, and tumor mutational burden. We quantified the spatial distribution of tumor-infiltrating CD8<sup>+</sup> T cells and coexpression of the T-cell-exhaustion marker thymocyte selection-associated high mobility group box (TOX) by digital immunoprofiling and quantified tertiary lymphoid structures. Most METs were pathologically “cold.” Inflamed, pathologically “hot” PTs were associated with decreased disease-free survival, worst for patients with high levels of CD8<sup>+</sup>TOX<sup>+</sup> T cells. Interestingly, inflamed METs showed a relative increase in exhausted CD8<sup>+</sup>TOX<sup>+</sup> T cells and increased accumulative size of tertiary lymphoid structures compared with PTs. Integrative analysis of molecular and immune phenotypes revealed <em>BAP1</em> and <em>CDKN2A/B</em> deficiency to be associated with an inflamed immune phenotype. Our results highlight the distinct spatial distribution and differentiation of CD8+ T cells at metastatic sites, and the association of an inflamed microenvironment with specific genomic alterations.</p></div>\",\"PeriodicalId\":18706,\"journal\":{\"name\":\"Modern Pathology\",\"volume\":null,\"pages\":null},\"PeriodicalIF\":7.1000,\"publicationDate\":\"2024-07-04\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"https://www.sciencedirect.com/science/article/pii/S0893395224001388/pdfft?md5=64710c524cf3d80798aa4ff621a2d88a&pid=1-s2.0-S0893395224001388-main.pdf\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"Modern Pathology\",\"FirstCategoryId\":\"3\",\"ListUrlMain\":\"https://www.sciencedirect.com/science/article/pii/S0893395224001388\",\"RegionNum\":1,\"RegionCategory\":\"医学\",\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"\",\"PubModel\":\"\",\"JCR\":\"Q1\",\"JCRName\":\"PATHOLOGY\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"Modern Pathology","FirstCategoryId":"3","ListUrlMain":"https://www.sciencedirect.com/science/article/pii/S0893395224001388","RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"PATHOLOGY","Score":null,"Total":0}
引用次数: 0
摘要
最近有人建议对转移性ccRCC患者采用辅助免疫疗法,但目前还没有组织生物标志物来预测ccRCC的治疗反应。潜在的预测性生物标志物主要在原发肿瘤组织中进行评估,而对转移瘤的研究仍然不足。为了探索原发肿瘤及其匹配转移灶的基因组改变和免疫表型之间的潜在差异,我们通过全面的靶向平行测序、全基因组拷贝数变异(CNV)分析、微卫星不稳定性(MSI)测定和肿瘤突变负荷(TMB)分析了47例ccRCC患者的原发肿瘤(PTs)及其匹配的远处转移灶(METs)。我们通过数字免疫谱分析量化了肿瘤浸润CD8+ T细胞的空间分布、T细胞衰竭标记物TOX的共表达,并量化了三级淋巴结构(TLS)。大多数 MET 在病理上是 "冷 "的。发炎的病理 "热 "PT与无病生存期(DFS)下降有关,CD8+TOX+ T细胞水平高的患者无病生存期最短。有趣的是,与PTs相比,发炎的METs显示耗竭的CD8+TOX+ T细胞相对增加,TLS的累积大小增加。分子和免疫表型的综合分析表明,BAP1 和 CDKN2A/B 缺乏与炎症免疫表型相关。我们的研究结果突显了 CD8+ T 细胞在转移部位的独特空间分布和分化,以及炎症微环境与特定基因组改变的关联。
Immune Phenotype-Genotype Associations in Primary Clear Cell Renal Cell Carcinoma and Matched Metastatic Tissue
Adjuvant immunotherapy has been recently recommended for patients with metastatic clear cell renal cell carcinoma (ccRCC), but there are no tissue biomarkers to predict treatment response in ccRCC. Potential predictive biomarkers are mainly assessed in primary tumor tissue, whereas metastases (METs) remain understudied. To explore potential differences between genomic alterations and immune phenotypes in primary tumors and their matched METs, we analyzed primary tumors (PTs) of 47 ccRCC patients and their matched distant METs by comprehensive targeted parallel sequencing, whole-genome copy number variation analysis, determination of microsatellite instability, and tumor mutational burden. We quantified the spatial distribution of tumor-infiltrating CD8+ T cells and coexpression of the T-cell-exhaustion marker thymocyte selection-associated high mobility group box (TOX) by digital immunoprofiling and quantified tertiary lymphoid structures. Most METs were pathologically “cold.” Inflamed, pathologically “hot” PTs were associated with decreased disease-free survival, worst for patients with high levels of CD8+TOX+ T cells. Interestingly, inflamed METs showed a relative increase in exhausted CD8+TOX+ T cells and increased accumulative size of tertiary lymphoid structures compared with PTs. Integrative analysis of molecular and immune phenotypes revealed BAP1 and CDKN2A/B deficiency to be associated with an inflamed immune phenotype. Our results highlight the distinct spatial distribution and differentiation of CD8+ T cells at metastatic sites, and the association of an inflamed microenvironment with specific genomic alterations.
期刊介绍:
Modern Pathology, an international journal under the ownership of The United States & Canadian Academy of Pathology (USCAP), serves as an authoritative platform for publishing top-tier clinical and translational research studies in pathology.
Original manuscripts are the primary focus of Modern Pathology, complemented by impactful editorials, reviews, and practice guidelines covering all facets of precision diagnostics in human pathology. The journal's scope includes advancements in molecular diagnostics and genomic classifications of diseases, breakthroughs in immune-oncology, computational science, applied bioinformatics, and digital pathology.