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

• Published in: Nature communications 2024-11, Vol.15 (1), p.10259-18, Article 10259
• Main Authors: Feng, Yu, Ma, Wenjuan, Zang, Yupeng, Guo, Yanying, Li, Young, Zhang, Yixuan, Dong, Xuan, Liu, Yi, Zhan, Xiaojuan, Pan, Zhizhong, Luo, Mei, Wu, Miaoqing, Chen, Ao, Kang, Da, Chen, Gong, Liu, Longqi, Zhou, Jingying, Zhang, Rongxin
• Format: Article
• Language: English
• Subjects: 38; 38/39; 38/91; 631/250/251; 631/67/1059/2325; 692/4028/67/1504/1885; Cancer; Cancer-Associated Fibroblasts - immunology; Cancer-Associated Fibroblasts - metabolism; Cancer-Associated Fibroblasts - pathology; Cellular structure; Colorectal cancer; Colorectal carcinoma; Colorectal Neoplasms - genetics; Colorectal Neoplasms - immunology; Colorectal Neoplasms - pathology; Colorectal Neoplasms - therapy; CXCL13 protein; DNA Mismatch Repair; Extracellular matrix; Female; Gene sequencing; High definition; Humanities and Social Sciences; Humans; Immune checkpoint inhibitors; Immune Checkpoint Inhibitors - pharmacology; Immune Checkpoint Inhibitors - therapeutic use; Immune status; Immune system; Immunotherapy; Immunotherapy - methods; Lymphocytes; Lymphocytes T; Male; Microenvironments; Mismatch repair; multidisciplinary; Science; Science (multidisciplinary); Sensitizing; Single-Cell Analysis; Stroma; Stromal Cells - immunology; Stromal Cells - pathology; Tumor microenvironment; Tumor Microenvironment - immunology; Tumors; Yeast
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-024-54710-3

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. Colorectal cancer patients with mismatch repair-deficient, but not MMR-proficient tend to benefit from immune checkpoint blockade therapy. Here, the authors identify interactions among tumor and immune cells that are associated with the responsiveness to immunotherapy in colorectal cancer.