PO.MCB09.06 · 分子与细胞生物学
Elevated plasma trimethylamine-N-oxide (TMAO) levels correlate with better clinical and molecular responses in immunotherapy-treated resectable gastroesophageal cancer and pleural mesothelioma
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摘要 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.