IDEAS home Printed from https://ideas.repec.org/a/nat/natcom/v13y2022i1d10.1038_s41467-022-35096-6.html
   My bibliography  Save this article

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
    as

    Download full text from publisher

    File URL: https://www.nature.com/articles/s41467-022-35096-6
    File Function: Abstract
    Download Restriction: no

    File URL: https://libkey.io/10.1038/s41467-022-35096-6?utm_source=ideas
    LibKey link: if access is restricted and if your library uses this service, LibKey will redirect you to where you can use your library subscription to access this item
    ---><---

    References listed on IDEAS

    as
    1. Giovanni Germano & Simona Lamba & Giuseppe Rospo & Ludovic Barault & Alessandro Magrì & Federica Maione & Mariangela Russo & Giovanni Crisafulli & Alice Bartolini & Giulia Lerda & Giulia Siravegna & B, 2017. "Inactivation of DNA repair triggers neoantigen generation and impairs tumour growth," Nature, Nature, vol. 552(7683), pages 116-120, December.
    2. Abhishek Tyagi & Sambad Sharma & Kerui Wu & Shih-Ying Wu & Fei Xing & Yin Liu & Dan Zhao & Ravindra Pramod Deshpande & Ralph B. D’Agostino & Kounosuke Watabe, 2021. "Nicotine promotes breast cancer metastasis by stimulating N2 neutrophils and generating pre-metastatic niche in lung," Nature Communications, Nature, vol. 12(1), pages 1-18, December.
    3. Stefanie K. Wculek & Ilaria Malanchi, 2015. "Neutrophils support lung colonization of metastasis-initiating breast cancer cells," Nature, Nature, vol. 528(7582), pages 413-417, December.
    4. Roser Vento-Tormo & Mirjana Efremova & Rachel A. Botting & Margherita Y. Turco & Miquel Vento-Tormo & Kerstin B. Meyer & Jong-Eun Park & Emily Stephenson & Krzysztof Polański & Angela Goncalves & Lucy, 2018. "Single-cell reconstruction of the early maternal–fetal interface in humans," Nature, Nature, vol. 563(7731), pages 347-353, November.
    Full references (including those not matched with items on IDEAS)

    Most related items

    These are the items that most often cite the same works as this one and are cited by the same works as this one.
    1. Lichun Ma & Sophia Heinrich & Limin Wang & Friederike L. Keggenhoff & Subreen Khatib & Marshonna Forgues & Michael Kelly & Stephen M. Hewitt & Areeba Saif & Jonathan M. Hernandez & Donna Mabry & Roman, 2022. "Multiregional single-cell dissection of tumor and immune cells reveals stable lock-and-key features in liver cancer," Nature Communications, Nature, vol. 13(1), pages 1-17, December.
    2. Junho Lee & Donggu Lee & Sean Lawler & Yangjin Kim, 2021. "Role of neutrophil extracellular traps in regulation of lung cancer invasion and metastasis: Structural insights from a computational model," PLOS Computational Biology, Public Library of Science, vol. 17(2), pages 1-29, February.
    3. Charlotte R. Bell & Victoria S. Pelly & Agrin Moeini & Shih-Chieh Chiang & Eimear Flanagan & Christian P. Bromley & Christopher Clark & Charles H. Earnshaw & Maria A. Koufaki & Eduardo Bonavita & Sant, 2022. "Chemotherapy-induced COX-2 upregulation by cancer cells defines their inflammatory properties and limits the efficacy of chemoimmunotherapy combinations," Nature Communications, Nature, vol. 13(1), pages 1-17, December.
    4. Jeff Yat-Fai Chung & Philip Chiu-Tsun Tang & Max Kam-Kwan Chan & Vivian Weiwen Xue & Xiao-Ru Huang & Calvin Sze-Hang Ng & Dongmei Zhang & Kam-Tong Leung & Chun-Kwok Wong & Tin-Lap Lee & Eric W-F Lam &, 2023. "Smad3 is essential for polarization of tumor-associated neutrophils in non-small cell lung carcinoma," Nature Communications, Nature, vol. 14(1), pages 1-17, December.
    5. Qian-Yue Zhang & Xiao-Ping Ye & Zheng Zhou & Chen-Fang Zhu & Rui Li & Ya Fang & Rui-Jia Zhang & Lu Li & Wei Liu & Zheng Wang & Shi-Yang Song & Sang-Yu Lu & Shuang-Xia Zhao & Jian-Nan Lin & Huai-Dong S, 2022. "Lymphocyte infiltration and thyrocyte destruction are driven by stromal and immune cell components in Hashimoto’s thyroiditis," Nature Communications, Nature, vol. 13(1), pages 1-18, December.
    6. Xi Li & Alfonso Poire & Kang Jin Jeong & Dong Zhang & Tugba Yildiran Ozmen & Gang Chen & Chaoyang Sun & Gordon B. Mills, 2024. "C5aR1 inhibition reprograms tumor associated macrophages and reverses PARP inhibitor resistance in breast cancer," Nature Communications, Nature, vol. 15(1), pages 1-20, December.
    7. Meng Liu & Mengjun Ji & Jianghong Cheng & Yingzhe Li & Yingpu Tian & Hui Zhao & Yang Wang & Sijing Zhu & Leilei Zhang & Xinmei Xu & Gen-Sheng Feng & Xiaohuan Liang & Haili Bao & Yedong Tang & Shuangbo, 2023. "Deciphering a critical role of uterine epithelial SHP2 in parturition initiation at single cell resolution," Nature Communications, Nature, vol. 14(1), pages 1-14, December.
    8. Adele M. Alchahin & Shenglin Mei & Ioanna Tsea & Taghreed Hirz & Youmna Kfoury & Douglas Dahl & Chin-Lee Wu & Alexander O. Subtelny & Shulin Wu & David T. Scadden & John H. Shin & Philip J. Saylor & D, 2022. "A transcriptional metastatic signature predicts survival in clear cell renal cell carcinoma," Nature Communications, Nature, vol. 13(1), pages 1-15, December.
    9. Zhongwei Xin & Mingjie Lin & Zhixing Hao & Di Chen & Yongyuan Chen & Xiaoke Chen & Xia Xu & Jinfan Li & Dang Wu & Ying Chai & Pin Wu, 2022. "The immune landscape of human thymic epithelial tumors," Nature Communications, Nature, vol. 13(1), pages 1-16, December.
    10. Lucía López & Luciano Gastón Morosi & Federica Terza & Pierre Bourdely & Giuseppe Rospo & Roberto Amadio & Giulia Maria Piperno & Valentina Russo & Camilla Volponi & Simone Vodret & Sonal Joshi & Fran, 2024. "Dendritic cell-targeted therapy expands CD8 T cell responses to bona-fide neoantigens in lung tumors," Nature Communications, Nature, vol. 15(1), pages 1-17, December.
    11. Md Tauhidul Islam & Lei Xing, 2023. "Cartography of Genomic Interactions Enables Deep Analysis of Single-Cell Expression Data," Nature Communications, Nature, vol. 14(1), pages 1-17, December.
    12. Clara Alsinet & Maria Nascimento Primo & Valentina Lorenzi & Erica Bello & Iva Kelava & Carla P. Jones & Roser Vilarrasa-Blasi & Carmen Sancho-Serra & Andrew J. Knights & Jong-Eun Park & Beata S. Wysp, 2022. "Robust temporal map of human in vitro myelopoiesis using single-cell genomics," Nature Communications, Nature, vol. 13(1), pages 1-17, December.
    13. Jake R. Thomas & Anna Appios & Emily F. Calderbank & Nagisa Yoshida & Xiaohui Zhao & Russell S. Hamilton & Ashley Moffett & Andrew Sharkey & Elisa Laurenti & Courtney W. Hanna & Naomi McGovern, 2023. "Primitive haematopoiesis in the human placenta gives rise to macrophages with epigenetically silenced HLA-DR," Nature Communications, Nature, vol. 14(1), pages 1-16, December.
    14. Ann-Christin Gnirck & Marie-Sophie Philipp & Alex Waterhölter & Malte Wunderlich & Nikhat Shaikh & Virginia Adamiak & Lena Henneken & Tobias Kautz & Tingting Xiong & Daniela Klaus & Pascal Tomczyk & M, 2023. "Mucosal-associated invariant T cells contribute to suppression of inflammatory myeloid cells in immune-mediated kidney disease," Nature Communications, Nature, vol. 14(1), pages 1-16, December.
    15. Taghreed Hirz & Shenglin Mei & Hirak Sarkar & Youmna Kfoury & Shulin Wu & Bronte M. Verhoeven & Alexander O. Subtelny & Dimitar V. Zlatev & Matthew W. Wszolek & Keyan Salari & Evan Murray & Fei Chen &, 2023. "Dissecting the immune suppressive human prostate tumor microenvironment via integrated single-cell and spatial transcriptomic analyses," Nature Communications, Nature, vol. 14(1), pages 1-20, December.
    16. Eric Buren & David Azzara & Javier Rangel-Moreno & Maria de la Luz Garcia-Hernandez & Shawn P. Murphy & Ethan D. Cohen & Ethan Lewis & Xihong Lin & Hae-Ryung Park, 2024. "Single-cell RNA sequencing reveals placental response under environmental stress," Nature Communications, Nature, vol. 15(1), pages 1-18, December.
    17. Chen Dong & Shuhua Fu & Rowan M. Karvas & Brian Chew & Laura A. Fischer & Xiaoyun Xing & Jessica K. Harrison & Pooja Popli & Ramakrishna Kommagani & Ting Wang & Bo Zhang & Thorold W. Theunissen, 2022. "A genome-wide CRISPR-Cas9 knockout screen identifies essential and growth-restricting genes in human trophoblast stem cells," Nature Communications, Nature, vol. 13(1), pages 1-16, December.
    18. Ariane F. Busso-Lopes & Leandro X. Neves & Guilherme A. Câmara & Daniela C. Granato & Marco Antônio M. Pretti & Henry Heberle & Fábio M. S. Patroni & Jamile Sá & Sami Yokoo & César Rivera & Romênia R., 2022. "Connecting multiple microenvironment proteomes uncovers the biology in head and neck cancer," Nature Communications, Nature, vol. 13(1), pages 1-24, December.
    19. Kate E. Stanley & Tatjana Jatsenko & Stefania Tuveri & Dhanya Sudhakaran & Lore Lannoo & Kristel Calsteren & Marie Borre & Ilse Parijs & Leen Coillie & Kris Bogaert & Rodrigo Almeida Toledo & Liesbeth, 2024. "Cell type signatures in cell-free DNA fragmentation profiles reveal disease biology," Nature Communications, Nature, vol. 15(1), pages 1-13, December.
    20. Javier Rodríguez-Ubreva & Anna Arutyunyan & Marc Jan Bonder & Lucía Del Pino-Molina & Stephen J. Clark & Carlos de la Calle-Fabregat & Luz Garcia-Alonso & Louis-François Handfield & Laura Ciudad & Edu, 2022. "Single-cell Atlas of common variable immunodeficiency shows germinal center-associated epigenetic dysregulation in B-cell responses," Nature Communications, Nature, vol. 13(1), pages 1-18, December.

    More about this item

    Statistics

    Access and download statistics

    Corrections

    All material on this site has been provided by the respective publishers and authors. You can help correct errors and omissions. When requesting a correction, please mention this item's handle: RePEc:nat:natcom:v:13:y:2022:i:1:d:10.1038_s41467-022-35096-6. See general information about how to correct material in RePEc.

    If you have authored this item and are not yet registered with RePEc, we encourage you to do it here. This allows to link your profile to this item. It also allows you to accept potential citations to this item that we are uncertain about.

    If CitEc recognized a bibliographic reference but did not link an item in RePEc to it, you can help with this form .

    If you know of missing items citing this one, you can help us creating those links by adding the relevant references in the same way as above, for each refering item. If you are a registered author of this item, you may also want to check the "citations" tab in your RePEc Author Service profile, as there may be some citations waiting for confirmation.

    For technical questions regarding this item, or to correct its authors, title, abstract, bibliographic or download information, contact: Sonal Shukla or Springer Nature Abstracting and Indexing (email available below). General contact details of provider: http://www.nature.com .

    Please note that corrections may take a couple of weeks to filter through the various RePEc services.

    IDEAS is a RePEc service. RePEc uses bibliographic data supplied by the respective publishers.