Integrating spatial transcriptomics, single-cell RNAseq, and multiplexed imaging, Feng and Ma et al. identified a well organized barrier-like structure in the tumor–stroma boundary that separated tumors from the immune aggregates and stroma in pMMR CRCs. Patients with dMMR CRC who experienced lower clinical benefit with anti-PD-1 therapy also displayed similar boundaries. CXCL14+ CAFs, potentially reacting to particular signals from tumor cells, were highly correlated with the structural barrier, which excluded T cells in the TME of ICB non-responders. Meanwhile, LAMP3+ DCs and CXCL13+ T cells accumulated in the tumor stroma boundary of ICB responders.
Contributed by Shishir Pant
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.
Author Info: (1) Shanxi Medical University-BGI Collaborative Center for Future Medicine, Shanxi Medical University, Taiyuan, 030001, China. BGI Research, Shenzhen, 519083, China. BGI Research,
Author Info: (1) Shanxi Medical University-BGI Collaborative Center for Future Medicine, Shanxi Medical University, Taiyuan, 030001, China. BGI Research, Shenzhen, 519083, China. BGI Research, Hangzhou, 310030, China. Guangdong Provincial Key Laboratory of Human Disease Genomics, Shenzhen Key Laboratory of Genomics, BGI Research, Shenzhen, 519083, China. (2) State Key Laboratory of Oncology in South China, Guangzhou, 510060, Guangdong, People's Republic of China. Department of Intensive Care Unit, Sun Yat-sen University Cancer Centre, Guangzhou, 510060, Guangdong, People's Republic of China. (3) College of Life Sciences, University of Chinese Academy of Sciences, 100049, Beijing, China. (4) BGI Research, Shenzhen, 519083, China. (5) BGI Research, Shenzhen, 519083, China. BGI Research, Hangzhou, 310030, China. (6) School of Biomedical Sciences, The Chinese University of Hong Kong, Hong Kong SAR, 999077, China. (7) BGI Research, Hangzhou, 310030, China. (8) BGI Research, Hangzhou, 310030, China. College of Life Sciences, University of Chinese Academy of Sciences, 100049, Beijing, China. (9) BGI Research, Shenzhen, 519083, China. College of Life Sciences, University of Chinese Academy of Sciences, 100049, Beijing, China. (10) State Key Laboratory of Oncology in South China, Guangzhou, 510060, Guangdong, People's Republic of China. Department of Colorectal Surgery, Sun Yat-sen University Cancer Centre, Guangzhou, 510060, Guangdong, People's Republic of China. (11) BGI Research, Hangzhou, 310030, China. College of Life Sciences, University of Chinese Academy of Sciences, 100049, Beijing, China. (12) State Key Laboratory of Oncology in South China, Guangzhou, 510060, Guangdong, People's Republic of China. Department of Colorectal Surgery, Sun Yat-sen University Cancer Centre, Guangzhou, 510060, Guangdong, People's Republic of China. (13) BGI Research, Shenzhen, 519083, China. BGI Research, Hangzhou, 310030, China. (14) State Key Laboratory of Oncology in South China, Guangzhou, 510060, Guangdong, People's Republic of China. Department of Colorectal Surgery, Sun Yat-sen University Cancer Centre, Guangzhou, 510060, Guangdong, People's Republic of China. (15) State Key Laboratory of Oncology in South China, Guangzhou, 510060, Guangdong, People's Republic of China. chengong@sysucc.org.cn. Department of Colorectal Surgery, Sun Yat-sen University Cancer Centre, Guangzhou, 510060, Guangdong, People's Republic of China. chengong@sysucc.org.cn. (16) Shanxi Medical University-BGI Collaborative Center for Future Medicine, Shanxi Medical University, Taiyuan, 030001, China. liulongqi@genomics.cn. BGI Research, Shenzhen, 519083, China. liulongqi@genomics.cn. BGI Research, Hangzhou, 310030, China. liulongqi@genomics.cn. (17) School of Biomedical Sciences, The Chinese University of Hong Kong, Hong Kong SAR, 999077, China. zhoujy@cuhk.edu.hk. (18) State Key Laboratory of Oncology in South China, Guangzhou, 510060, Guangdong, People's Republic of China. zhangrx@sysucc.org.cn. Department of Colorectal Surgery, Sun Yat-sen University Cancer Centre, Guangzhou, 510060, Guangdong, People's Republic of China. zhangrx@sysucc.org.cn.
