Spatially organized tumor-stroma boundary determines the efficacy of immunotherapy in colorectal cancer patients
Colorectal cancer (CRC) patients with mismatch repair (MMR)-deficient (dMMR) but not MMR-proficient (pMMR) tend to benefit from immune checkpoint blockade (ICB) therapy. To profile the tumor microenvironments (TME) underlying these varied therapeutic responses, we integrate spatial enhanced resolution omics-sequencing (Stereo-seq), single-cell RNA sequencing, and multiplexed imaging analysis to create high-definition spatial maps of tumors from treatment-naïve and ICB-treated CRC patients. Our results identify the spatial organization and immune status of the tumor-stroma boundary as a distinctive feature of dMMR and pMMR CRCs, which associates with ICB response. The physical interactions and abundance of LAMP3<sup>+</sup>DCs and CXCL13<sup>+</sup>T cells may shape the ICB-responsive tumor-stroma boundary, whereas CXCL14<sup>+</sup>cancer-associated fibroblasts tend to remodel extracellular matrix to form a structural barrier in non-responders. Our work therefore points out the importance of the molecular and cellular spatial structures of tumors in ICB response, raising the possibility of reprogramming tumor-stroma boundary for sensitizing immunotherapies in the majority of CRCs.
Authors
- Jingying Zhou (ORCID: https://orcid.org/0000-0002-9740-6159)
- Da Kang
- Mei Luo (ORCID: https://orcid.org/0000-0002-0183-2373)
- Longqi Liu (ORCID: https://orcid.org/0000-0002-5828-5542)
- Xiaojuan Zhan
- Yupeng Zang (ORCID: https://orcid.org/0000-0002-5098-1172)
- Young Li
- Yixuan Zhang (ORCID: https://orcid.org/0009-0005-2915-9538)
- Rongxin Zhang (ORCID: https://orcid.org/0000-0001-5498-0428)
- Yanying Guo (ORCID: https://orcid.org/0000-0002-7623-4423)
- Miaoqing Wu
- Xuan Dong (ORCID: https://orcid.org/0000-0001-8288-322X)
- Yi Liu (ORCID: https://orcid.org/0000-0002-8801-9317)
- Ao Chen (ORCID: https://orcid.org/0000-0002-9699-8340)
- Gong Chen (ORCID: https://orcid.org/0000-0002-5067-9889)
- Yu Feng (ORCID: https://orcid.org/0000-0001-8358-8740)
- Zhizhong Pan (ORCID: https://orcid.org/0000-0002-5198-2919)
- Wenjuan Ma
Institutions
- BGI Group (China) (CN)
- Sun Yat-sen University (CN)
- Shanxi Medical University (CN)
- Chinese University of Hong Kong (HK)
- Key Laboratory of Guangdong Province (CN)
- Sun Yat-sen University Cancer Center (CN)
- University of Chinese Academy of Sciences (CN)
- BGI Research (CN)
- State Key Laboratory of Oncology in South China
Publication Details
- Journal
- Nature Communications
- Published
- 2024-11-26
- DOI
- https://doi.org/10.1038/s41467-024-54710-3
- Citations
- 51
- Primary Topic
- Cancer Immunotherapy and Biomarkers
- Type
- article
- Field-Weighted Citation Impact
- 14.41
Funders
- Guangzhou Medical University
- National Natural Science Foundation of China
- Sun Yat-sen University
- Chinese Society of Clinical Oncology
- State Key Laboratory of Oncology in South China
- Basic and Applied Basic Research Foundation of Guangdong Province