Multi-omics of the gut microbial ecosystem in patients with microsatellite-instability-high gastrointestinal cancer resistant to immunotherapy
Siyuan Cheng, Zihan Han, Die Dai, Fang Li, Xiaotian Zhang, Ming Lu, Zhihao Lü, Xicheng Wang, Jun Zhou, Jian Li, Xiaohuan Guo, Panwei Song, Chuangzhao Qiu, Wei Shen, Qi Zhang, Ning Zhu, Xi Wang, Yan Tan, Yan Kou, Xiaochen Yin, Lin Shen, Zhi Peng
Abstract
Despite the encouraging efficacy of anti-PD-1/PD-L1 immunotherapy in microsatellite-instability-high/deficient mismatch repair (MSI-H/dMMR) advanced gastrointestinal cancer, many patients exhibit primary or acquired resistance. Using multi-omics approaches, we interrogate gut microbiome, blood metabolome, and cytokines/chemokines of patients with MSI-H/dMMR gastrointestinal cancer (N = 77) at baseline and during the treatment. We identify a number of microbes (e.g., Porphyromonadaceae) and metabolites (e.g., arginine) highly associated with primary resistance to immunotherapy. An independent validation cohort (N = 39) and mouse model are used to further confirm our findings. A predictive machine learning model for primary resistance is also built and achieves an accuracy of 0.79 on the external validation set. Furthermore, several microbes are pinpointed that gradually changed during the process of acquired resistance. In summary, our study demonstrates the essential role of gut microbiome in drug resistance, and this can be utilized as a preventative diagnosis tool and therapeutic target in the future.