Spatial transcriptomics analysis of neoadjuvant cabozantinib and nivolumab in advanced hepatocellular carcinoma identifies independent mechanisms of resistance and recurrence

肿瘤微环境 卡波扎尼布 医学 癌症研究 肝细胞癌 无容量 癌相关成纤维细胞 免疫疗法 肿瘤进展 免疫系统 癌症 内科学 免疫学
作者
Shuming Zhang,Long Yuan,Ludmila Danilova,Guanglan Mo,Qingfeng Zhu,Atul Deshpande,Alexander T.F. Bell,Jennifer H. Elisseeff,Aleksander S. Popel,Robert A. Anders,Elizabeth M. Jaffee,Mark Yarchoan,Elana J. Fertig,Luciane T. Kagohara
出处
期刊:Genome Medicine [Springer Nature]
卷期号:15 (1) 被引量:37
标识
DOI:10.1186/s13073-023-01218-y
摘要

Abstract Background Novel immunotherapy combination therapies have improved outcomes for patients with hepatocellular carcinoma (HCC), but responses are limited to a subset of patients. Little is known about the inter- and intra-tumor heterogeneity in cellular signaling networks within the HCC tumor microenvironment (TME) that underlie responses to modern systemic therapy. Methods We applied spatial transcriptomics (ST) profiling to characterize the tumor microenvironment in HCC resection specimens from a prospective clinical trial of neoadjuvant cabozantinib, a multi-tyrosine kinase inhibitor that primarily blocks VEGF, and nivolumab, a PD-1 inhibitor in which 5 out of 15 patients were found to have a pathologic response at the time of resection. Results ST profiling demonstrated that the TME of responding tumors was enriched for immune cells and cancer-associated fibroblasts (CAF) with pro-inflammatory signaling relative to the non-responders. The enriched cancer-immune interactions in responding tumors are characterized by activation of the PAX5 module, a known regulator of B cell maturation, which colocalized with spots with increased B cell marker expression suggesting strong activity of these cells. HCC-CAF interactions were also enriched in the responding tumors and were associated with extracellular matrix (ECM) remodeling as there was high activation of FOS and JUN in CAFs adjacent to the tumor. The ECM remodeling is consistent with proliferative fibrosis in association with immune-mediated tumor regression. Among the patients with major pathologic responses, a single patient experienced early HCC recurrence. ST analysis of this clinical outlier demonstrated marked tumor heterogeneity, with a distinctive immune-poor tumor region that resembles the non-responding TME across patients and was characterized by HCC-CAF interactions and expression of cancer stem cell markers, potentially mediating early tumor immune escape and recurrence in this patient. Conclusions These data show that responses to modern systemic therapy in HCC are associated with distinctive molecular and cellular landscapes and provide new targets to enhance and prolong responses to systemic therapy in HCC.
最长约 10秒,即可获得该文献文件

科研通智能强力驱动
Strongly Powered by AbleSci AI
更新
大幅提高文件上传限制,最高150M (2024-4-1)

科研通是完全免费的文献互助平台,具备全网最快的应助速度,最高的求助完成率。 对每一个文献求助,科研通都将尽心尽力,给求助人一个满意的交代。
实时播报
刚刚
朴素完成签到 ,获得积分10
1秒前
多C多快乐完成签到 ,获得积分10
1秒前
搜集达人应助现代百招采纳,获得10
1秒前
kinizu完成签到,获得积分10
1秒前
2秒前
allen完成签到,获得积分10
4秒前
欣喜的香彤完成签到,获得积分10
4秒前
4秒前
kinizu发布了新的文献求助50
5秒前
喜羊羊完成签到 ,获得积分10
5秒前
云雾完成签到 ,获得积分10
5秒前
浮流少年完成签到,获得积分10
6秒前
6秒前
abc完成签到 ,获得积分10
6秒前
7秒前
orixero应助XIXI采纳,获得10
7秒前
科研通AI2S应助科研通管家采纳,获得10
9秒前
乐乐应助科研通管家采纳,获得10
9秒前
无花果应助科研通管家采纳,获得10
9秒前
今后应助科研通管家采纳,获得10
9秒前
彭于晏应助科研通管家采纳,获得10
9秒前
几酌应助科研通管家采纳,获得10
9秒前
爆米花应助科研通管家采纳,获得10
9秒前
Jasper应助科研通管家采纳,获得10
9秒前
Jun应助科研通管家采纳,获得30
9秒前
Nancy完成签到,获得积分10
9秒前
小蘑菇应助科研通管家采纳,获得10
9秒前
wking应助科研通管家采纳,获得20
9秒前
9秒前
香蕉觅云应助科研通管家采纳,获得10
9秒前
小蘑菇应助科研通管家采纳,获得10
9秒前
CodeCraft应助科研通管家采纳,获得10
9秒前
Reese完成签到 ,获得积分10
9秒前
bkagyin应助科研通管家采纳,获得10
9秒前
几酌应助科研通管家采纳,获得10
9秒前
失眠星星完成签到,获得积分10
9秒前
小马甲应助叉叉采纳,获得10
10秒前
Yang发布了新的文献求助10
11秒前
Jewl完成签到,获得积分10
13秒前
高分求助中
Becoming: An Introduction to Jung's Concept of Individuation 600
Ore genesis in the Zambian Copperbelt with particular reference to the northern sector of the Chambishi basin 500
A new species of Coccus (Homoptera: Coccoidea) from Malawi 500
A new species of Velataspis (Hemiptera Coccoidea Diaspididae) from tea in Assam 500
PraxisRatgeber: Mantiden: Faszinierende Lauerjäger 500
Die Gottesanbeterin: Mantis religiosa: 656 400
Mantiden: Faszinierende Lauerjäger Faszinierende Lauerjäger 400
热门求助领域 (近24小时)
化学 医学 生物 材料科学 工程类 有机化学 生物化学 物理 内科学 纳米技术 计算机科学 化学工程 复合材料 基因 遗传学 催化作用 物理化学 免疫学 量子力学 细胞生物学
热门帖子
关注 科研通微信公众号,转发送积分 3165183
求助须知:如何正确求助?哪些是违规求助? 2816164
关于积分的说明 7911772
捐赠科研通 2475878
什么是DOI,文献DOI怎么找? 1318401
科研通“疑难数据库(出版商)”最低求助积分说明 632143
版权声明 602388