PO.MCB09.06 · 分子与细胞生物学

血浆氧化三甲胺（TMAO）水平升高与免疫治疗的可切除胃食管癌和胸膜间皮瘤中更好的临床和分子应答相关

Elevated plasma trimethylamine-N-oxide (TMAO) levels correlate with better clinical and molecular responses in immunotherapy-treated resectable gastroesophageal cancer and pleural mesothelioma

编号 4724 展板 22 时间 4/21 09:00–12:00 区域 Section 22 主讲 Rachel Keogh, MS

分会场 Metabolic Alterations in Colorectal and Gastrointestinal Cancers

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作者与单位 Authors & Affiliations

Rachel J. Keogh¹, Paul K. Lee¹, N.V. Rajeshkumar¹, Blair V. Landon¹, Joshua E. Reuss², Jaime Wehr¹, Gavin Pereira¹, Amna Jamali¹, Noushin Niknafs¹, Ronan J. Kelly³, Ali H. Zaidi⁴, Josephine L. Feliciano¹, Julie R. Brahmer¹, Vincent K. Lam¹, Patrick M. Forde¹, Chi V. Dang¹, Valsamo Anagnostou¹

¹Johns Hopkins University School of Medicine, Baltimore, MD,²Georgetown Univ. School of Medicine, Washington, WA,³Charles A. Sammons Cancer Center Baylor University Medical Center, Dallas, TX,⁴Allegheny Health Network Cancer Institute, Pittsburgh, PA

摘要 Abstract

中文摘要

背景：微生物组来源的代谢物已显示出对免疫治疗应答的显著影响，尤其是在免疫检查点阻断（ICB）的背景下。氧化三甲胺（TMAO）是肠道细菌代谢膳食胆碱时产生的一种胺氧化物，在临床前研究中已被确定可增强抗肿瘤免疫应答。在此，我们评估了接受新辅助ICB的可切除癌症患者中循环胆碱代谢物与临床结局和循环肿瘤DNA（ctDNA）残留病灶的关系。方法：通过液相色谱-质谱（SCIEX Triple Quad 6500+）定量了51例接受新辅助ICB的I-III期弥漫性胸膜间皮瘤（DPM；n=25例患者；NCT03918252）或II/III期食管/胃食管交界处癌（E/GEJ；n=26例患者；NCT03044613）患者治疗前的胆碱、三甲胺（TMA）和TMAO血浆浓度。跨代谢物阈值比较临床结局，以及通过肿瘤指导的无细胞DNA（cfDNA）全基因组测序（WGS）比较ctDNA残留病灶。DPM队列中的ctDNA残留病灶通过肿瘤（n=28）、白细胞（n=28）和血浆（n=97）WGS的交集进行测量。结果：在DPM队列中，基线胆碱、TMA和TMAO的中位浓度分别为3970、2840和256 ng/mL。较高的基线TMAO水平与C2D1（Fisher精确检验，p=0.028）、C3D1（Fisher精确检验，p=0.057）和术前（Fisher精确检验，p=0.01）较低的ctDNA残留病灶相关。此外，TMAO较高的患者在整个新辅助窗口期ctDNA不可检测，或cfDNA肿瘤分数从基线到术前降低≥95%（Fisher精确检验，p=0.028）。在该队列中，ctDNA残留病灶与无进展生存期和总生存期密切相关（对数秩检验，p<0.05）。在E/GEJ队列中，基线胆碱、TMA和TMAO的中位浓度分别为279、2945和4175 ng/mL。获得主要病理应答的患者TMAO水平在数值上更高（Fisher精确检验，p=0.078）。与DPM队列中的发现一致，E/GEJ队列中TMAO较低（最低五分位数；<197 ng/mL）的患者与TMAO浓度较高（≥197 ng/mL）的患者相比，总生存期更短（对数秩检验，p=0.034），在校正临床病理变量后这一关联仍显著（Cox多变量分析，p=0.04）。结论：我们的发现表明，较高的血浆TMAO水平可能与分子ctDNA应答和新辅助ICB更好的临床结局相关，进一步支持了胆碱代谢物在增强免疫治疗应答中潜在的免疫调节作用。

查看英文原文 English abstract

Background: Microbiome-derived metabolites have demonstrated significant impact on immunotherapy response, particularly in the context of immune checkpoint blockade (ICB). Trimethylamine-N-oxide (TMAO), an amine oxide generated when gut bacteria metabolize dietary choline, has been identified in preclinical studies to enhance anti-tumor immune responses. Here, we evaluated circulating choline metabolites with respect to clinical outcomes and circulating tumor DNA (ctDNA) residual disease in patients with resectable cancers receiving neoadjuvant ICB. Methods: Pre-treatment choline, trimethylamine (TMA) and TMAO plasma concentrations from 51 patients with stage I-III diffuse pleural mesothelioma (DPM; n = 25 patients; NCT03918252) or stage II/III esophageal/gastro-esophageal junction cancer (E/GEJ; n = 26 patients; NCT03044613) on neoadjuvant ICB, were quantified via liquid chromatography-mass spectrometry (SCIEX Triple Quad 6500+). Clinical outcomes were compared across metabolite thresholds, as were ctDNA residual disease through tumor-informed cell-free DNA (cfDNA) whole-genome sequencing (WGS). ctDNA residual disease in the DPM cohort was measured by intersecting tumor (n = 28), white blood cell (n = 28), and plasma (n = 97) WGS. Results: In the DPM cohort, median baseline choline, TMA and TMAO concentrations were 3970, 2840 and 256 ng/mL, respectively. Higher baseline TMAO levels were associated with lower ctDNA residual disease at C2D1 (Fisher's exact, p = 0.028), C3D1 (Fisher's exact, p = 0.057) and pre-surgery (Fisher's exact, p = 0.01). Further, patients with higher TMAO had either undetectable ctDNA throughout the neoadjuvant window or ≥95% reduction in cfDNA tumor fraction from baseline to pre-surgery (Fisher's exact, p = 0.028). In this cohort, ctDNA residual disease strongly correlated with progression-free and overall survival (log-rank, p < 0.05). In the E/GEJ cohort, median baseline choline, TMA and TMAO concentrations were 279, 2945 and 4175 ng/mL, respectively. Patients who attained a major pathologic response had numerically higher TMAO levels (Fisher's exact, p = 0.078). In line with the findings in the DPM cohort, patients in the E/GEJ cohort with lower TMAO (lowest quintile; <197 ng/mL) had shorter overall survival (log-rank, p = 0.034) compared to those with higher TMAO concentration ( ≥197 ng/mL), an association that remained significant after adjusting for clinicopathological variables (Cox multivariable, p = 0.04). Conclusion: Our findings indicate that higher plasma TMAO levels may be linked to molecular ctDNA response and better clinical outcomes with neoadjuvant ICB, further supporting a potential immunomodulatory role of choline metabolites in enhancing immunotherapy response.

利益披露 Disclosure

R. J. Keogh, MSD Travel. P. K. Lee, None.. N. Rajeshkumar, None. J. E. Reuss, Genentech/Roche ). Verastem ). Nuvalent ). Arcus ). Revolution Medicines ). Regeneron ), Other, Consultant/Advisory Role. Amgen ). AstraZeneca ), Other, Consultant/Advisory Role. DualityBio ). Daiichi Sankyo Other, Consultant/Advisory Role. Seagen Other, Consultant/Advisory Role. Gilead Other, Consultant/Advisory Role. Janssen Other, Consultant/Advisory Role. Novocure Other, Consultant/Advisory Role. Bristol Myer Squibbs Other, Consultant/Advisory Role. Summit Therapeutics Other, Consultant/Advisory Role. Pfizer Other, Consultant/Advisory Role. Eli Lilly Other, Consultant/Advisory Role. Natera Other, Consultant/Advisory Role. Merck Other, Consultant/Advisory Role, EMD Serono - Consultant/Advisory Role, Roche Diagnostics - Consultant/Advisory Role, Boehringer Ingelheim - Consultant/Advisory Role. J. Wehr, None.. G. Pereira, None.. A. Jamali, None.. N. Niknafs, None. R. J. Kelly, Amgen Consultant/Advisory Role. Astellas Other, Consultant/Advisory Role. AstraZeneca Other, Consultant/Advisory Role. Beigene Other, Consultant/Advisory Role. Bristol Myers Squibb ), Other, Consultant/Advisory Role. Cardinal Health Other, Consultant/Advisory Role. Daiichi Sankyo Other, Consultant/Advisory Role. Eisai Other, Consultant/Advisory Role. Eli Lilly ), Other, Consultant/Advisory Role. EMD Serono Other, Consultant/Advisory Role. Exact Sciences Other, Consultant/Advisory Role. Grail Other, Consultant/Advisory Role. Illumina Other, Consultant/Advisory Role. Ipsen Other, Consultant/Advisory Role. Merck Other, Consultant/Advisory Role. Novartis Other, Consultant/Advisory Role. Novocure Other, Consultant/Advisory Role. Oncohost Other, Consultant/Advisory Role. Phillips Other, Consultant/Advisory Role. Takeda Other, Consultant/Advisory Role, Toray - Consultant/Advisory Role. A. H. Zaidi, Eli Lilly ). Previse Stock, Other, Consultant/Advisory Role. Prognomiq ), Other, Consultant/Advisory Role. Gilead Other, Consultant/Advisory Role. Delfi Diagnostics ), Other, Consultant/Advisory Role. BilliontoOne ), Other, Consultant/Advisory Role. Genece Health ). Roche ). Tempus ). Myriad Genetics ). Gritstone Bio Stock. Tg Therapeutics Stock. J. L. Feliciano, AstraZeneca ), Other, Consultant/Advisory Role. Bristol Myers Squibb ). Coherus Biosciences Other, Consultant/Advisory Role. Daiichi Sankyo Other, Consultant/Advisory Role. Genentech Other, Consultant/Advisory Role. Janssen Other, Consultant/Advisory Role. Eli Lilly Other, Consultant/Advisory Role. Regeneron Other, Consultant/Advisory Role. Pfizer ). Takeda Other, Consultant/Advisory Role. J. R. Brahmer, AstraZeneca ), Other, Consultant/Advisory role. Bristol Myers Squibb ). RAPT Therapeutics Other, Consultant/Advisory role. Mestag Other, Consultant/Advisory role. GlaxoSmithKline Other, Consultant/Advisory role. Amgen Other, Consultant/Advisory role. Sanofi Aventis Other, Consultant/Advisory role. Summit Therapeutics Other, Consultant/Advisory role. Genentech Other, Consultant/Advisory role. Bayer Other, Consultant/Advisory role. Genmab Data Safety and Monitoring Board. V. K. Lam, Iovance Biotherapeutics Other, Consulting. Anheart Therapeutics Consulting. Takeda Consulting. Seattle Genetics ), Other, Consulting. Bristol Myers Squibb ), Other, Consulting. AstraZeneca ), Other, Consulting. Guardant Health Other, Consulting. GlaxoSmithKline ). Merck ). P. M. Forde, AstraZeneca ), Other, Consultant/Advisory Role. Bristol Myers Squibb ), Other, Consultant/Advisory Role. Novartis ), Other, Consultant/Advisory Role. Regeneron ). Kyowa ). BioNTech ), Other, Consultant/Advisory Role. AbbVie Other, Consultant/Advisory Role. Amgen Other, Consultant/Advisory Role. Ascendis Other, Consultant/Advisory Role. ChromaCode Other, Consultant/Advisory Role. Daiichi Sankyo Other, Consultant/Advisory Role. F-Star Other, Consultant/Advisory Role. Genelux Other, Consultant/Advisory Role. Gilead Other, Consultant/Advisory Role. iTeos Other, Consultant/Advisory Role. Novocure Other, Consultant/Advisory Role. Regeneron Other, Consultant/Advisory Role. Tavotek Other, Consultant/Advisory Role. Teva Other, Consultant/Advisory Role. Genentech Other, Consultant/Advisory Role, Sanofi - Consultant/Advisory Role, Surface - Consultant/Advisory Role, Janssen - Consultant/Advisory Role, G1 - Consultant/Advisory Role, Merck - Consultant/Advisory Role, Polaris - Data Safety Monitoring Board, Flame - Data Safety Monitoring Board. C. V. Dang, None. V. Anagnostou, Astra Zeneca ), Other, Advisory Board. Bristol-Myers Squibb ). Personal Genome Diagnostics/Labcorp ), Other, Honoraria. Delfi Diagnostics ). Neogenomics Other, Advisory Board. Foundation Medicine Other, Honoraria. Roche Other, Honoraria. Guardant Health Other, Honoraria. ThermoFisher Other, Honoraria.

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