PO.CL01.14 · 临床研究

透明细胞肾细胞癌（ccRCC）免疫治疗前后的空间多组学分析鉴定出新的可成药靶点

Spatial multi-omics profiling of clear cell renal cell carcinoma (ccRCC) pre-and post-immunotherapy identifies new druggable targets

编号 6684 展板 26 时间 4/21 02:00–05:00 区域 Section 48 主讲 Navneet Kaur, PhD

分会场 Spatial Proteomics and Transcriptomics 3

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作者与单位 Authors & Affiliations

Navneet Kaur¹, Wadih Issa¹, Ze Yu², Hua Zhong³, Aleksandra Weronika Nielsen⁴, Jay Jasti⁴, Shahed Abdullah¹, Libin Yan¹, Damla Gunenc¹, Qinhan Zhou¹, Andrew DeVilbiss¹, Satwik Rajaram⁴, Payal Kapur³, Chao Xing⁵, Liwei Jia³, Andrew Z. Wang⁶, Tian Zhang¹

¹Department of Internal Medicine (Division of Hematology-Oncology), Harold C. Simmons Comprehensive Cancer Center, UT Southwestern Medical Center, Dallas, TX,²Eugene McDermott Center for Human Growth and Development, UT Southwestern Medical Center, Dallas, TX,³Department of Pathology, UT Southwestern Medical Center, Dallas, TX,⁴Lyda Hill Department of Bioinformatics, UT Southwestern Medical Center, Dallas, TX,⁵Lyda Hill Department of Bioinformatics; O'Donnell School of Public Health, Eugene McDermott Center for Human Growth and Development, UT Southwestern Medical Center, Dallas, TX,⁶Department of Radiation Oncology, Harold C. Simmons Comprehensive Cancer Center, University of Texas Southwestern Medical Center, Dallas, TX

摘要 Abstract

中文摘要

引言：免疫治疗（IO）和靶向VEGF的TKI已经改变了晚期ccRCC患者的预后。然而，对于IO治疗后的耐药机制知之甚少。方法：本研究纳入了15例具有治疗前和治疗后（Tx，IO-IO或IO-TKI）肿瘤样本的晚期ccRCC患者（pts）。使用Nanostring GeoMx空间分析平台对肿瘤进行分析。每例患者选择4至12个感兴趣区域（ROI），并将这些ROI进一步分割为肿瘤（PanCK+）、免疫（CD45+）和基质（PanCK-、CD45-）区室。采用基因集富集分析（GSEA）评估差异表达的基因和蛋白。利用CIBERSORT对整体基因表达进一步进行解卷积，以分析免疫细胞亚群。深度学习算法分析H&E切片的血管生成、免疫基因特征以及非负矩阵分解（NMF）聚类。结果：在肿瘤区室（PanCK+）中，若干具有临床可成药性的靶点，如Axl、HER2、TROP-2、GITR、HIF-1alpha和FGFR2，在IO后显著上调。有趣的是，Trop-2表达在IO-IO治疗后上调（Log2FC 0.038，p<0.01），但在IO-TKI后未上调（Log2FC -0.070，p<0.01）。一些接受IO/TKI的患者在治疗后肿瘤血管生成表达降低。NMF聚类将6/15例患者的治疗后样本归类为NMF4（IO-TKI队列10例中的4例，IO-IO队列5例中的2例）。NMF聚类3在大多数患者中于IO后仍持续存在。虽然大多数IO前样本具有中到高度的免疫浸润，但IO后样本的浸润水平更高。值得注意的是，CIBERSORT分析显示IO后免疫抑制性调节性T细胞（Treg）的比例降低（IO-TKI，p<0.01），而细胞毒性CD8+ T细胞在两个治疗队列中均增加（IO-TKI，p<0.01）。然而，仅在IO-IO治疗的亚组中，静息NK细胞显著增加（p=0.29），而活化NK细胞显著减少（p<0.01）。结论：IO为基础的治疗后RCC中的分子基因表达变化鉴定出了残余肿瘤中的临床靶点。NMF聚类4的持续存在、CD8+浸润以及Treg比例的降低提示IO后免疫细胞的扩增或持续存在。NMF聚类3和静息NK细胞比例的增加可能解释了IO后残余肿瘤的耐药性。鉴于RCC的异质性，对个体肿瘤进行分析以改善IO治疗结局势在必行。正在进行的分析包括IHC靶点验证。

查看英文原文 English abstract

Introduction: Immunotherapy (IO) and VEGF targeting TKIs have transformed outcomes of patients with advanced ccRCC. However, much less is known about treatment resistance mechanisms after IO therapy. Methods: 15 patients (pts) with advanced ccRCC who had tumor samples pre- and post-treatment (Tx, IO-IO or IO-TKI) were included in this study. Tumors were profiled using the Nanostring GeoMx spatial profiling platform. 4 to 12 regions of interest (ROIs) were selected for each patient, and the ROIs were further segmented into tumor (PanCK+), immune (CD45+), and stroma (PanCk-, CD45-) compartments. Differentially expressed genes and proteins were assessed with Gene Set Enrichment Analysis (GSEA). Bulk gene expression was further deconvoluted to profile immune cell subsets using CIBERSORT. Deep learning algorithms analyzed H&E slides for angiogenic, immune gene signatures, and non-negative matrix factorization (NMF) clustering. Results: In the tumor compartment (PanCK+), several clinically druggable targets such as Axl, HER2, TROP-2, GITR, HIF-1alpha, and FGFR2 were significantly upregulated after IO. Interestingly, Trop-2 expression was upregulated in IO-IO (Log2FC 0.038, p<0.01) post-Tx but not after IO-TKI (Log2FC -0.070, p<0.01). Some patients who received IO/TKIs had decreased tumor angiogenic expression post-Tx. NMF clustering classified post-Tx as NMF4 in 6/15 patients (4 of 10 in IO-TKI cohort and 2 of 5 in IO-IO cohort). NMF cluster 3 remained post-IO in most patients.While most pre-IO samples had moderate to high immune infiltration, post-IO samples had even higher levels. Notably, CIBERSORT profiling revealed post-IO proportion of immune suppressive regulatory T cells were decreased (IO-TKI, p <0.01), while cytotoxic CD8+ T cells were increased (IO-TKI, p <0.01) with both Tx cohorts. However, resting NK cells were increased (p=0.29), while activated NK cells were decreased (p <0.01) significantly only in IO-IO treated subsets. Conclusion: Molecular gene expression changes in RCC after IO-based therapy identified clinical targets in residual tumors. NMF cluster 4 persistence, CD8+ infiltration, and reduction in Treg proportion suggests an expansion or persistence of immune cells post-IO. NMF cluster 3 and increased proportion of resting NK cells may explain the resistance of residual tumor post-IO. Given the heterogeneity in RCC, it is imperative to profile individual tumors to improve IO therapy outcomes. Ongoing analyses include IHC target validation.

利益披露 Disclosure

N. Kaur, None.. W. Issa, None.. Z. Yu, None.. H. Zhong, None.. A. W. Nielsen, None.. J. Jasti, None.. S. Abdullah, None.. L. Yan, None.. D. Gunenc, None.. Q. Zhou, None.. A. DeVilbiss, None.. S. Rajaram, None.. P. Kapur, None.. C. Xing, None.. L. Jia, None. A. Z. Wang, Capio biosciences Other, Co-founder. T. Zhang, Merck ), Other, Advisory Board/consultant. Eli lilly ), Other, Advisory Board/consultant. Janssen ), Other, Advisory Board/consultant. AstraZeneca ), Other, Advisory Board/consultant. Pfizer ), Other, Advisory Board/consultant. Tempus ). ALX Oncology ). Janus Therapeutics ). OncoC4 ). Exelixius ). Bayer ). Kura Oncology ). Sanofi-Aventis Other, Advisory Board/consultant. Bristol Myers Squibb Other, Advisory Board/consultant. Novartis Other, Advisory Board/consultant. Gilead Other, Advisory Board/consultant. EMD Serono Other, Advisory Board/consultant. Dava Oncology Other, Advisory Board/consultant. Aptitude health Other, Advisory Board/consultant. MJH Associates Other, Advisory Board/consultant.

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