PO.CL09.01 · 临床研究

肿瘤重塑通路在肥胖相关结直肠癌的肿瘤微环境中富集

Tumor remodeling pathways are enriched in the tumor microenvironment of obesity-associated colorectal cancer

编号 5348 展板 16 时间 4/21 09:00–12:00 区域 Section 46 主讲 Yu Fujiwara, MD

分会场 Precision Oncology and Real World Data

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作者与单位 Authors & Affiliations

Yu Fujiwara¹, Sarbajit Mukherjee², Yali Zhang¹, Jianmin Wang¹, Emily Baiyee Toegel³, Tiago Biachi De Castria⁴, Bodour Salhia⁵, Anne M. Noonan⁶, Michael J. Cavnar⁷, Dae Won Kim⁴, Muneeb Rehman⁸, Patrick B. Boland⁹, Melissa L. Fishel¹⁰, Carlos H.F. Chan¹¹, Michele M. Gage¹², Hassan Hatoum¹³, Julia White¹⁴, Robert J. Rounbehler¹⁵, Michelle Churchman¹⁵, Deepak Vadehra¹

¹Roswell Park Comprehensive Cancer Center, Buffalo, NY,²Miami Cancer Institute, Baptist Health South Florida, Miami, FL,³University of Colorado Cancer Center, Aurora, CO,⁴Moffitt Cancer Center, Tampa, FL,⁵USC Norris Comprehensive Cancer Center, Los Angeles, CA,⁶Ohio State University, Columbus, OH,⁷Markey Cancer Center, Lexington, KY,⁸University of Virginia, Charlottesville, VA,⁹Rutgers Cancer Institute, New Brunswick, NJ,¹⁰IU Simon Comprehensive Cancer Center, Indianapolis, IN,¹¹Carver College of Medicine, University of Iowa, Iowa City, IA,¹²Murtha Cancer Center, Bethesda, MD,¹³Oklahoma University Stephenson Cancer Center, Oklahoma City, OK,¹⁴University of Kansas Cancer Center, Kansas City, KS,¹⁵Aster Insights, Tampa, FL

摘要 Abstract

中文摘要

背景：肥胖是已知的结直肠癌（CRC）危险因素，可促进全身性炎症和T细胞功能障碍，然而肥胖相关CRC肿瘤免疫微环境（TIME）的特征尚未明确界定。因此，我们进行了一项全面分析，以刻画肥胖相关CRC独特的免疫学和基因组学特征。方法：我们对按体重指数（BMI）分层的CRC患者进行了基因组学和转录组学分析——肥胖（BMI≥30）、超重（25≤BMI<30）、正常（18≤BMI<25）和体重过轻（BMI<18）。数据来自肿瘤学研究信息交换网络（ORIEN）。进行差异基因表达（DGE）分析和基因集富集分析（GSEA），以识别差异表达的免疫相关基因和改变的生物学通路；使用CIBERSORT进行免疫解卷积，以探究肿瘤免疫微环境组成。同时，探究基因组数据，使用Fisher精确检验比较所选基因（APC、KRAS、TP53、SMAD4、PIK3CA、BRAF、NRAS、TGFBR2、MLH1、MSH2、MSH6、PMS2、CTNNB1和PTEN）的改变频率。统计模型对年龄、性别和疾病分期等协变量进行了校正，以分离肥胖的影响。结果：共纳入939例患者（肥胖：n=355；超重：n=326；正常：n=242；体重过轻：n=16）。随着体重增加，男性性别更为常见（p<0.0001），但疾病分期在各BMI组间分布均衡（p=0.581）。GSEA显示，肥胖与组织重塑相关通路显著相关，包括上皮-间质转化、凝血和血管生成。相反，正常体重状态的特征为代谢过程的上调，如氧化磷酸化和脂肪酸代谢，以及调控细胞周期进程和DNA修复的通路（标准化富集评分≥2.0，校正p值<0.05）。尽管通过免疫解卷积得出的免疫细胞组成在肥胖组与正常体重组之间无差异，但DGE分析显示，肥胖组中若干免疫检查点相关基因（如CD276（B7H3）和SIRPalpha（CD47配体））的表达较高，而正常体重组中CD73（NT5E）和凋亡诱导基因TNFSF10（TRAIL）的表达较高。所选基因的改变频率在肥胖组与正常组之间无显著差异。结论：伴肥胖的CRC以肿瘤重塑为特征，而不伴肥胖的CRC在肿瘤微环境（TME）中有更多上调的代谢过程。伴肥胖和不伴肥胖病例之间关键免疫检查点的差异表达状态可能提示该疾病实体中量身定制的治疗靶点。

查看英文原文 English abstract

Background: Obesity is a known risk factor for colorectal cancer (CRC) that promotes systemic inflammation and T-cell dysfunction, yet the characteristics of the tumor immune microenvironment (TIME) in obesity-associated CRC are not well-defined. Therefore, we performed a comprehensive analysis to characterize the unique immunological and genomic features of obesity-associated CRC. Methods: We performed genomic and transcriptomic analyses of patients with CRC stratified by body mass index (BMI) - obese (BMI ≥30), overweight (25≤ BMI <30), normal (18≤ BMI <25), and underweight (BMI<18). Data were obtained from the Oncology Research Information Exchange Network (ORIEN). Differential gene expression (DGE) and gene set enrichment analyses (GSEA) were performed to identify differentially expressed immune-related genes and altered biological pathways; immune deconvolution was performed to explore tumor immune microenvironment composition using CIBERSORT. Concurrently, genomic data were explored to compare the alteration frequency of selected genes ( APC, KRAS, TP53, SMAD4, PIK3CA, BRAF, NRAS, TGFBR2, MLH1, MSH2, MSH6, PMS2, CTNNB1, and PTEN ) using a Fisher's exact test. Statistical models were adjusted for covariates such as age, gender, and disease stage to isolate the effects of obesity. Results: Overall, 939 patients (obese: n=355; overweight: n=326; normal: n=242; underweight: n=16) were included. Male sex was more common as weight increases (p<0.0001) but disease stage was well balanced across BMI groups (p=0.581). GSEA revealed that obesity was significantly associated with pathways related to tissue remodeling, including epithelial-mesenchymal transition, coagulation, and angiogenesis. Conversely, normal weight status was characterized by the upregulation of metabolic processes such as oxidative phosphorylation and fatty acid metabolism, alongside pathways governing cell cycle progression and DNA repair (normalized enrichment score ≥ 2.0, adjusted p value <0.05). Although immune cell compositions via immune deconvolution did not differ between obese and normal weight groups, DGE analysis revealed higher expression of several immune checkpoint related genes such as CD276 (B7H3) and SIRPalpha (CD47 ligand) in the obesity group and CD73 (NT5E) and apoptosis-inducing gene, TNFSF10 (TRAIL) in the normal weight. The alteration frequency of selected genes was not significantly different between obese and normal groups. Conclusions: CRC with obesity is characterized by tumor remodeling whereas CRC without obesity had more upregulated metabolic processes in the TME. Differential expression status of key immune checkpoints between cases with and without obesity could indicate a tailored therapeutic target in this disease entity.

利益披露 Disclosure

Y. Fujiwara, Johnson & Johnson ). American Association for Cancer Research ). Japanese Medical Society of America Other, Scholarship. S. Mukherjee, American Society of Clinical Oncology Other, volunteer guidelines panel member. National Comprehensive Cancer Network ). Ipsen Biopharmaceuticals ). North American Neuroendocrine Tumor Society ). Merck ). Bristol Myers Squibb ). Eisai ). BeiGene Ltd ). Y. Zhang, None.. J. Wang, None.. E. B. Toegel, None. T. Biachi De Castria, Bayer Independent Contractor. Moderna Independent Contractor. AstraZeneca Independent Contractor. Ipsen Travel. Moderna Travel. Ipsen ). Astellas ). A. M. Noonan, Hexagon Independent Contractor. Revolution Medicines Independent Contractor. Jazz Pharmaceuticals Independent Contractor. Astra Zeneca Independent Contractor. Dava Oncology Travel. M. J. Cavnar, None.. D. Kim, None.. M. Rehman, None. P. B. Boland, Taiho Oncology Independent Contractor. BMS Independent Contractor. Beigene Independent Contractor. Abbvie Independent Contractor. Incyte Independent Contractor. M. M. Gage, None.. H. Hatoum, None.. J. White, None.. M. Churchman, None.. D. Vadehra, None.

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