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- 조회155
울산대학교 의과대학, 서울아산병원
Genome Med., May 30 2026, | https://doi.org/10.1186/s13073-026-01680-4
Dynamics of tumor ecosystems and microbiome in response to neoadjuvant ABFOLFOX treatment in patients with unresectable colorectal cancer with liver metastasis
Wonkyung Kim 1,2, Jeong Eun Kim 3, Yong Sang Hong 3, Dae Wook Hwang 4, Jihun Kim 2, Ji Sung Lee 5, Jin Ho Shin 2, Tae Won Kim 3, Deepti Nagarkar 6, Allyson Byrd 6, Chang Ohk Sung 1,2,7,* and Sun Young Kim 3,*
1Department of Medical Science, Brain Korea 21 project, Asan Medical Institute of Convergence Science and Technology, University of Ulsan College of Medicine, Seoul, Republic of Korea.
2Department of Pathology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea.
3Department of Oncology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea.
4Division of Hepatobiliary and Pancreatic Surgery, Department of Surgery, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea.
5Department of Clinical Epidemiology and Biostatistics, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea.
6Department of Cancer Immunology, Genentech, Inc., South San Francisco, CA, USA.
7Bioinformatics Core Laboratory, Convergence Medicine Research Center, Asan Institute for Life Sciences, Asan Medical Center, Seoul, Republic of Korea.
2Department of Pathology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea.
3Department of Oncology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea.
4Division of Hepatobiliary and Pancreatic Surgery, Department of Surgery, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea.
5Department of Clinical Epidemiology and Biostatistics, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea.
6Department of Cancer Immunology, Genentech, Inc., South San Francisco, CA, USA.
7Bioinformatics Core Laboratory, Convergence Medicine Research Center, Asan Institute for Life Sciences, Asan Medical Center, Seoul, Republic of Korea.
*Corresponding authors: correspondence to Chang Ohk Sung or Sun Young Kim
Abstract
Background
This study aims to explore the effects of neoadjuvant atezolizumab, bevacizumab, leucovorin, 5-fluorouracil, and oxaliplatin (ABFOLFOX) in patients with unresectable colorectal liver metastases (CRLM), focusing on the molecular dynamics of tumor ecosystems (TE) of CRLM and their impact on treatment outcomes.
Methods
The study comprises two cohorts with CRLM tissue samples analyzed with RNA sequencing and immunohistochemical staining: cross-sectional cohort A (n = 60, CRLM treated with or without neoadjuvant chemotherapy) and prospectively registered cohort B (n = 20 with serial sampling and treated with ABFOLFOX). Shotgun metagenomic sequencing was performed for stool samples from cohort B.
Results
Durable disease control (PFS ≥ 24 months) was observed in 35% (7/20) of patients receiving ABFOLFOX. Analysis revealed a progressive increase in the immunogenic microenvironment within CRLM tissues upon the addition of therapeutic agents, specifically bevacizumab, and the most significant TE changes in CRLM were observed in those treated with ABFOLFOX in cohort B. The monocyte lineage was significantly associated with benefit from ABFOLFOX. Good responders exhibited improved immune response and notable activation of the SP140 transcription factor regulon. Moreover, microbiome analysis revealed that high abundance of Prevotella was positively correlated with good response and enhanced immune environment within the tumor. Causal mediation analysis suggested that the gut microbiome partially links the ABFOLFOX treatment response to the tumor microenvironment.
Conclusions
ABFOLFOX enhances the TE immune profile of CRLM, which is further augmented by the gut-liver axis characterized by Prevotella abundance, and can induce durable disease control in a subgroup of patients.
This study aims to explore the effects of neoadjuvant atezolizumab, bevacizumab, leucovorin, 5-fluorouracil, and oxaliplatin (ABFOLFOX) in patients with unresectable colorectal liver metastases (CRLM), focusing on the molecular dynamics of tumor ecosystems (TE) of CRLM and their impact on treatment outcomes.
Methods
The study comprises two cohorts with CRLM tissue samples analyzed with RNA sequencing and immunohistochemical staining: cross-sectional cohort A (n = 60, CRLM treated with or without neoadjuvant chemotherapy) and prospectively registered cohort B (n = 20 with serial sampling and treated with ABFOLFOX). Shotgun metagenomic sequencing was performed for stool samples from cohort B.
Results
Durable disease control (PFS ≥ 24 months) was observed in 35% (7/20) of patients receiving ABFOLFOX. Analysis revealed a progressive increase in the immunogenic microenvironment within CRLM tissues upon the addition of therapeutic agents, specifically bevacizumab, and the most significant TE changes in CRLM were observed in those treated with ABFOLFOX in cohort B. The monocyte lineage was significantly associated with benefit from ABFOLFOX. Good responders exhibited improved immune response and notable activation of the SP140 transcription factor regulon. Moreover, microbiome analysis revealed that high abundance of Prevotella was positively correlated with good response and enhanced immune environment within the tumor. Causal mediation analysis suggested that the gut microbiome partially links the ABFOLFOX treatment response to the tumor microenvironment.
Conclusions
ABFOLFOX enhances the TE immune profile of CRLM, which is further augmented by the gut-liver axis characterized by Prevotella abundance, and can induce durable disease control in a subgroup of patients.
논문정보
- Research article
- 2026년 05월 (BRIC 등록일 2026-06-01)
- 국내(교신)+국외 연구진
- 의약학 > 유전 및 유전체의학
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