Inflammation promotes resistance to immune checkpoint inhibitors in high microsatellite instability colorectal cancer

Qiaoqi Sui, Xi Zhang, Chao Chen, Jinghua Tang, Jiehai Yu, Weihao Li, Kai Han, Wu Jiang, Leen Liao, Lingheng Kong, Yuan Li, Zhenlin Hou, Chi Zhou, Chenzhi Zhang, Linjie Zhang, Binyi Xiao, Weijian Mei, Yanbo Xu, Jiayi Qin, Jian Zheng, Zhizhong Pan and Pei-Rong Ding ()
Additional contact information
Qiaoqi Sui: Sun Yat-sen University Cancer Center
Xi Zhang: BGI-Shenzhen
Chao Chen: Peking University Shenzhen Hospital; Shenzhen Peking University-The Hong Kong University of Science and Technology Medical Center
Jinghua Tang: Sun Yat-sen University Cancer Center
Jiehai Yu: Sun Yat-sen University Cancer Center
Weihao Li: Sun Yat-sen University Cancer Center
Kai Han: Sun Yat-sen University Cancer Center
Wu Jiang: Sun Yat-sen University Cancer Center
Leen Liao: Sun Yat-sen University Cancer Center
Lingheng Kong: Sun Yat-sen University Cancer Center
Yuan Li: Sun Yat-sen University Cancer Center
Zhenlin Hou: Sun Yat-sen University Cancer Center
Chi Zhou: Sun Yat-sen University Cancer Center
Chenzhi Zhang: Sun Yat-sen University Cancer Center
Linjie Zhang: Sun Yat-sen University Cancer Center
Binyi Xiao: Sun Yat-sen University Cancer Center
Weijian Mei: Sun Yat-sen University Cancer Center
Yanbo Xu: Sun Yat-sen University Cancer Center
Jiayi Qin: State Key Laboratory of Oncology in South China
Jian Zheng: State Key Laboratory of Oncology in South China
Zhizhong Pan: Sun Yat-sen University Cancer Center
Pei-Rong Ding: Sun Yat-sen University Cancer Center

Nature Communications, 2022, vol. 13, issue 1, 1-11

Abstract: Abstract Inflammation is a common medical complication in colorectal cancer (CRC) patients, which plays significant roles in tumor progression and immunosuppression. However, the influence of inflammatory conditions on the tumor response to immune checkpoint inhibitors (ICI) is incompletely understood. Here we show that in a patient with high microsatellite instability (MSI-H) CRC and a local inflammatory condition, the primary tumor progresses but its liver metastasis regresses upon Pembrolizumab treatment. In silico investigation prompted by this observation confirms correlation between inflammatory conditions and poor tumor response to PD-1 blockade in MSI-H CRCs, which is further validated in a cohort of 62 patients retrospectively enrolled to our study. Inhibition of local but not systemic immune response is verified in cultures of paired T cells and organoid cells from patients. Single-cell RNA sequencing suggests involvement of neutrophil leukocytes via CD80/CD86-CTLA4 signaling in the suppressive immune microenvironment. In concordance with this finding, elevated neutrophil-to-lymphocyte ratio indicates inhibited immune status and poor tumor response to ICIs. Receiver operating characteristic curve further demonstrates that both inflammatory conditions and a high NLR could predict a poor response to ICIs in MSI- CRCs, and the predictive value could be further increased when these two predictors are combined. Our study thus suggests that inflammatory conditions in MSI-H CRCs correlate with resistance to ICIs through neutrophil leukocyte associated immunosuppression and proposes both inflammatory conditions and high neutrophil-to-lymphocyte ratio as clinical features for poor ICI response.

Date: 2022
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DOI: 10.1038/s41467-022-35096-6

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