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

Author

Listed:
  • Qiaoqi Sui

    (Sun Yat-sen University Cancer Center
    State Key Laboratory of Oncology in South China
    Collaborative Innovation Center for Cancer Medicine)

  • 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
    State Key Laboratory of Oncology in South China
    Collaborative Innovation Center for Cancer Medicine)

  • Jiehai Yu

    (Sun Yat-sen University Cancer Center
    State Key Laboratory of Oncology in South China
    Collaborative Innovation Center for Cancer Medicine)

  • Weihao Li

    (Sun Yat-sen University Cancer Center
    State Key Laboratory of Oncology in South China
    Collaborative Innovation Center for Cancer Medicine)

  • Kai Han

    (Sun Yat-sen University Cancer Center
    State Key Laboratory of Oncology in South China
    Collaborative Innovation Center for Cancer Medicine)

  • Wu Jiang

    (Sun Yat-sen University Cancer Center
    State Key Laboratory of Oncology in South China
    Collaborative Innovation Center for Cancer Medicine)

  • Leen Liao

    (Sun Yat-sen University Cancer Center
    State Key Laboratory of Oncology in South China
    Collaborative Innovation Center for Cancer Medicine)

  • Lingheng Kong

    (Sun Yat-sen University Cancer Center
    State Key Laboratory of Oncology in South China
    Collaborative Innovation Center for Cancer Medicine)

  • Yuan Li

    (Sun Yat-sen University Cancer Center
    State Key Laboratory of Oncology in South China
    Collaborative Innovation Center for Cancer Medicine)

  • Zhenlin Hou

    (Sun Yat-sen University Cancer Center
    State Key Laboratory of Oncology in South China
    Collaborative Innovation Center for Cancer Medicine)

  • Chi Zhou

    (Sun Yat-sen University Cancer Center
    State Key Laboratory of Oncology in South China
    Collaborative Innovation Center for Cancer Medicine)

  • Chenzhi Zhang

    (Sun Yat-sen University Cancer Center
    State Key Laboratory of Oncology in South China
    Collaborative Innovation Center for Cancer Medicine)

  • Linjie Zhang

    (Sun Yat-sen University Cancer Center
    State Key Laboratory of Oncology in South China
    Collaborative Innovation Center for Cancer Medicine)

  • Binyi Xiao

    (Sun Yat-sen University Cancer Center
    State Key Laboratory of Oncology in South China
    Collaborative Innovation Center for Cancer Medicine)

  • Weijian Mei

    (Sun Yat-sen University Cancer Center
    State Key Laboratory of Oncology in South China
    Collaborative Innovation Center for Cancer Medicine)

  • Yanbo Xu

    (Sun Yat-sen University Cancer Center
    State Key Laboratory of Oncology in South China
    Collaborative Innovation Center for Cancer Medicine)

  • Jiayi Qin

    (State Key Laboratory of Oncology in South China
    Collaborative Innovation Center for Cancer Medicine
    Sun Yat-sen University Cancer Center)

  • Jian Zheng

    (State Key Laboratory of Oncology in South China
    Collaborative Innovation Center for Cancer Medicine
    Sun Yat-sen University Cancer Center)

  • Zhizhong Pan

    (Sun Yat-sen University Cancer Center
    State Key Laboratory of Oncology in South China
    Collaborative Innovation Center for Cancer Medicine)

  • Pei-Rong Ding

    (Sun Yat-sen University Cancer Center
    State Key Laboratory of Oncology in South China
    Collaborative Innovation Center for Cancer Medicine)

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.

Suggested Citation

  • 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, 2022. "Inflammation promotes resistance to immune checkpoint inhibitors in high microsatellite instability colorectal cancer," Nature Communications, Nature, vol. 13(1), pages 1-11, December.
  • Handle: RePEc:nat:natcom:v:13:y:2022:i:1:d:10.1038_s41467-022-35096-6
    DOI: 10.1038/s41467-022-35096-6
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