Spatially organized tumor-stroma boundary determines the efficacy of immunotherapy in colorectal cancer patients

Yu Feng, Wenjuan Ma, Yupeng Zang, Yanying Guo, Young Li, Yixuan Zhang, Xuan Dong, Yi Liu, Xiaojuan Zhan, Zhizhong Pan, Mei Luo, Miaoqing Wu, Ao Chen, Da Kang, Gong Chen (), Longqi Liu (), Jingying Zhou () and Rongxin Zhang ()
Additional contact information
Yu Feng: Shanxi Medical University
Wenjuan Ma: Guangzhou
Yupeng Zang: University of Chinese Academy of Sciences
Yanying Guo: BGI Research
Young Li: BGI Research
Yixuan Zhang: The Chinese University of Hong Kong
Xuan Dong: BGI Research
Yi Liu: BGI Research
Xiaojuan Zhan: BGI Research
Zhizhong Pan: Guangzhou
Mei Luo: BGI Research
Miaoqing Wu: Guangzhou
Ao Chen: BGI Research
Da Kang: Guangzhou
Gong Chen: Guangzhou
Longqi Liu: Shanxi Medical University
Jingying Zhou: The Chinese University of Hong Kong
Rongxin Zhang: Guangzhou

Nature Communications, 2024, vol. 15, issue 1, 1-18

Abstract: Abstract 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+DCs and CXCL13+T cells may shape the ICB-responsive tumor-stroma boundary, whereas CXCL14+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.

Date: 2024
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DOI: 10.1038/s41467-024-54710-3

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