PO.IM02.03 · 免疫学

在异质性患者群体中T细胞炎症基因表达谱评分与肿瘤相关微生物组对结直肠癌死亡率的相互作用

Interaction between T-cell inflamed gene expression profile score and tumor-associated microbiome on colorectal cancer mortality in a heterogeneous patient population

编号 2867 展板 7 时间 4/20 02:00–05:00 区域 Section 9 主讲 Meredith Hullar, PhD

分会场 Microbiome, Inflammation, and Response to Immunotherapy in Cancer

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作者与单位 Authors & Affiliations

Claire Elizabeth Thomas¹, Hang Yin¹, Jeroen Huyghe¹, Nicole Catalina Lorona², Scott D. Labrie¹, Keith R. Curtis¹, Orsalem Kahsai¹, Sosun Nayemi¹, Ningxin Ma³, Timothy Randolph³, Conghui Qu¹, Sushma Thomas¹, Li Hsu¹, Amanda L. Koehne⁴, Heather Green-Mantrana⁵, Marc Matrana⁵, James J. Tiesinga⁶, William M. Grady¹, Diana Redwood⁷, Christopher I. Li¹, Li Li⁵, Riki (Ulrike) Peters¹, Jane C. Figueiredo², Timothy K. Thomas⁷, Amanda I. Phipps⁸, Meredith A. Hullar¹

¹Public Health Sciences, Fred Hutchinson Cancer Center, Seattle, WA,²Cedars-Sinai Medical Center, Los Angeles, CA,³Clinical Research Division, Fred Hutchinson Cancer Center, Seattle, WA,⁴Experimental Histopathology, Fred Hutchinson Cancer Center, Seattle, WA,⁵Ochsner Health System, New Orleans, LA,⁶Alaska Native Medical Center, Anchorage, AK,⁷Alaska Native Tribal Health Consortium, Anchorage, AK,⁸Department of Epidemiology, University of Washington, Seattle, WA

摘要 Abstract

中文摘要

背景：微生物组和肿瘤免疫反应是与结直肠癌（CRC）预后相关的重要且相互关联的组成部分。然而，这些组成部分之间的关联及其对CRC死亡率的潜在联合效应仍不清楚。方法：我们纳入了来自"人群间癌症差异转化研究项目"（TRPCDP）的366例CRC参与者（106例非裔美国人、161例阿拉斯加原住民、91例西班牙裔、8例非西班牙裔白人）。241例未死于CRC的参与者按年龄、性别、肿瘤部位、肿瘤分期、诊断年份和人群组别与125例在随访期间死于CRC的参与者进行匹配。我们对16S rRNA细菌基因V4区的微生物DNA进行测序，并使用Illumina TruSeq RNA Exome试剂盒对来自福尔马林固定石蜡包埋（FFPE）肿瘤组织的RNA进行测序。我们将T细胞炎症基因表达谱（GEP）评分计算为18个基因经log₂转换的每百万转录本的加权总和：CCL5、CD27、CD274（PD-L1）、CD276（B7-H3）、CD8A、CMKLR1、CXCL9、CXCR6、HLA-DQA1、HLA-DRB1、HLA-E、IDO1、LAG3、NKG7、PDCD1LG2（PDL2）、PSMB10、STAT1和TIGIT。我们以最高三分位数为阈值将T细胞炎症GEP评分二分为高、低两组。使用逻辑回归，我们估计了细菌存在与二分T细胞炎症GEP评分之间关联的比值比（OR）和95%置信区间（CI），以及细菌与二分T细胞炎症GEP评分对CRC特异性死亡率的交互效应，并校正匹配因素。结果：在检测的48个菌属中，Anaerococcus与较低的高T细胞炎症GEP评分几率相关（OR=0.34，95% CI 0.20-0.58），而Leptotrichia与较高的高T细胞炎症GEP评分几率相关（OR=2.93，95% CI 1.66-5.22）。合并时，肿瘤为Leptotrichia阳性且T细胞炎症GEP评分低的联合效应，相比Leptotrichia阴性且T细胞炎症GEP评分高的肿瘤，与超过四倍的CRC死亡几率相关（OR=4.41，95% CI 1.86-10.83）。结论：Leptotrichia存在与低T细胞炎症GEP评分的联合效应导致CRC死亡几率显著升高。理解这种免疫-微生物群相互作用的影响可能改善CRC预后分层，并有助于发现改善CRC预后的新治疗靶点。

查看英文原文 English abstract

Background: The microbiome and tumor immune response are important and inter-related components that are implicated in colorectal cancer (CRC) prognosis. However, associations between these components and potential joint effects on CRC mortality remain unclear. Methods: We included 366 participants with CRC (106 African American, 161 Alaska Native, 91 Hispanic, 8 non-Hispanic White) from the Translational Research Program in Cancer Differences across Populations (TRPCDP). 241 participants who did not die of CRC were matched to 125 participants who died of CRC during follow-up by age, sex, tumor site, tumor stage, year of diagnosis, and population group. We sequenced microbial DNA from the V4 region of the 16S rRNA bacterial gene and sequenced RNA using the Illumina TruSeq RNA Exome kit from formalin-fixed paraffin embedded (FFPE) tumor tissue. We calculated the T-cell inflamed gene expression profile (GEP) score as a weighted sum of log 2 -transformed transcripts per million of 18 genes: CCL5, CD27, CD274 (PD-L1), CD276 (B7-H3), CD8A, CMKLR1, CXCL9, CXCR6, HLA-DQA1, HLA-DRB1, HLA-E, IDO1, LAG3, NKG7, PDCD1LG2 (PDL2), PSMB10, STAT1, and TIGIT. We dichotomized the T-cell inflamed GEP score into high and low groups using the top tertile as a threshold. Using logistic regression, we estimated odds ratios (OR) and 95% confidence intervals (CI) for associations between bacterial presence and dichotomized T-cell inflamed GEP score, as well as interaction effects of bacteria and dichotomized T-cell inflamed GEP score on CRC-specific mortality, adjusting for matching factors. Results: Among 48 genera tested, Anaerococcus was associated with lower odds of high T-cell inflamed GEP score (OR=0.34, 95% CI 0.20-0.58) and Leptotrichia was associated with higher odds of high T-cell inflamed GEP score (OR=2.93, 95% CI 1.66-5.22). When combined, the joint effect of tumors being Leptotrichia positive and low T-cell inflamed GEP score was associated with over four times the odds of CRC mortality (OR=4.41, 95% CI 1.86-10.83) compared to tumors that were Leptotrichia negative and high T-cell inflamed GEP score. Conclusions: The joint effect of Leptotrichia presence and low T-cell inflamed GEP score resulted in markedly higher odds of CRC death. Understanding the influence of this immune-microbiota interaction may improve CRC prognostic stratification and enable the discovery of new treatment targets to improve CRC prognosis.

利益披露 Disclosure

C. E. Thomas, None.. H. Yin, None.. J. Huyghe, None.. N. C. Lorona, None.. S. D. Labrie, None.. K. R. Curtis, None.. O. Kahsai, None.. S. Nayemi, None.. N. Ma, None.. T. Randolph, None.. C. Qu, None.. S. Thomas, None.. L. Hsu, None.. A. L. Koehne, None.. H. Green-Mantrana, None.. M. Matrana, None.. J. J. Tiesinga, None.. W. M. Grady, None.. D. Redwood, None.. C. I. Li, None.. L. Li, None.. R. Peters, None.. J. C. Figueiredo, None.. T. K. Thomas, None.. A. I. Phipps, None.. M. A. Hullar, None.

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