IDEAS home Printed from https://ideas.repec.org/a/nat/natcom/v13y2022i1d10.1038_s41467-022-29026-9.html
   My bibliography  Save this article

Cell death-induced immunogenicity enhances chemoimmunotherapeutic response by converting immune-excluded into T-cell inflamed bladder tumors

Author

Listed:
  • Fotis Nikolos

    (Cedars-Sinai Medical Center)

  • Kazukuni Hayashi

    (Cedars-Sinai Medical Center
    Baylor College of Medicine)

  • Xen Ping Hoi

    (Cedars-Sinai Medical Center
    Cedars-Sinai Medical Center)

  • Mark Ellie Alonzo

    (Cedars-Sinai Medical Center
    Cedars-Sinai Medical Center)

  • Qianxing Mo

    (H. Lee Moffitt Cancer Center and Research Institute)

  • Armine Kasabyan

    (Cedars-Sinai Medical Center)

  • Hideki Furuya

    (Cedars-Sinai Medical Center
    Cedars-Sinai Medical Center)

  • Jane Trepel

    (National Cancer Institute)

  • Dolores Vizio

    (Cedars-Sinai Medical Center
    Cedars-Sinai Medical Center)

  • Jlenia Guarnerio

    (Cedars-Sinai Medical Center)

  • Dan Theodorescu

    (Cedars-Sinai Medical Center
    Cedars-Sinai Medical Center
    Cedars-Sinai Medical Center)

  • Charles Rosser

    (Cedars-Sinai Medical Center
    Cedars-Sinai Medical Center)

  • Andrea Apolo

    (National Cancer Institute)

  • Matthew Galsky

    (Icahn School of Medicine at Mount Sinai)

  • Keith Syson Chan

    (Cedars-Sinai Medical Center
    Cedars-Sinai Medical Center)

Abstract

Chemoimmunotherapy has recently failed to demonstrate significant clinical benefit in advanced bladder cancer patients; and the mechanism(s) underlying such suboptimal response remain elusive. To date, most studies have focused on tumor-intrinsic properties that render them “immune-excluded”. Here, we explore an alternative, drug-induced mechanism that impedes therapeutic response via disrupting the onset of immunogenic cell death. Using two immune-excluded syngeneic mouse models of muscle-invasive bladder cancer (MIBC), we show that platinum-based chemotherapy diminishes CD8+ T cell tumor infiltration and constraines their antitumoral activity, despite expression of activation markers IFNγ and granzyme B. Mechanistically, chemotherapy induces the release of prostaglandin E2 (PGE2) from dying cancer cells, which is an inhibitory damage-associated molecular pattern (iDAMP) that hinderes dendritic cell maturation. Upon pharmaceutical blockade of PGE2 release, CD8+ T cells become tumoricidal and display an intraepithelial-infiltrating (or inflamed) pattern. This “iDAMP blockade” approach synergizes with chemotherapy and sensitizes bladder tumors towards anti-PD1 immune checkpoint inhibitor therapy. These findings provide a compelling rationale to evaluate this drug combination in future clinical trials.

Suggested Citation

  • Fotis Nikolos & Kazukuni Hayashi & Xen Ping Hoi & Mark Ellie Alonzo & Qianxing Mo & Armine Kasabyan & Hideki Furuya & Jane Trepel & Dolores Vizio & Jlenia Guarnerio & Dan Theodorescu & Charles Rosser , 2022. "Cell death-induced immunogenicity enhances chemoimmunotherapeutic response by converting immune-excluded into T-cell inflamed bladder tumors," Nature Communications, Nature, vol. 13(1), pages 1-16, December.
  • Handle: RePEc:nat:natcom:v:13:y:2022:i:1:d:10.1038_s41467-022-29026-9
    DOI: 10.1038/s41467-022-29026-9
    as

    Download full text from publisher

    File URL: https://www.nature.com/articles/s41467-022-29026-9
    File Function: Abstract
    Download Restriction: no

    File URL: https://libkey.io/10.1038/s41467-022-29026-9?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. K. Hayashi & F. Nikolos & Y. C. Lee & A. Jain & E. Tsouko & H. Gao & A. Kasabyan & H. E. Leung & A. Osipov & S. Y. Jung & A. V. Kurtova & K. S. Chan, 2020. "Tipping the immunostimulatory and inhibitory DAMP balance to harness immunogenic cell death," Nature Communications, Nature, vol. 11(1), pages 1-13, December.
    2. Paul C. Tumeh & Christina L. Harview & Jennifer H. Yearley & I. Peter Shintaku & Emma J. M. Taylor & Lidia Robert & Bartosz Chmielowski & Marko Spasic & Gina Henry & Voicu Ciobanu & Alisha N. West & M, 2014. "PD-1 blockade induces responses by inhibiting adaptive immune resistance," Nature, Nature, vol. 515(7528), pages 568-571, November.
    3. Antonina V. Kurtova & Jing Xiao & Qianxing Mo & Senthil Pazhanisamy & Ross Krasnow & Seth P. Lerner & Fengju Chen & Terrence T. Roh & Erica Lay & Philip Levy Ho & Keith Syson Chan, 2015. "Blocking PGE2-induced tumour repopulation abrogates bladder cancer chemoresistance," Nature, Nature, vol. 517(7533), pages 209-213, January.
    4. Sanjeev Mariathasan & Shannon J. Turley & Dorothee Nickles & Alessandra Castiglioni & Kobe Yuen & Yulei Wang & Edward E. Kadel III & Hartmut Koeppen & Jillian L. Astarita & Rafael Cubas & Suchit Jhunj, 2018. "TGFβ attenuates tumour response to PD-L1 blockade by contributing to exclusion of T cells," Nature, Nature, vol. 554(7693), pages 544-548, February.
    5. Yu-Cheng Lee & Antonina V. Kurtova & Jing Xiao & Fotis Nikolos & Kazukuni Hayashi & Zoe Tramel & Antrix Jain & Fengju Chen & Mithil Chokshi & Ciaran Lee & Gang Bao & Xiang Zhang & Jianjun Shen & Qianx, 2019. "Collagen-rich airway smooth muscle cells are a metastatic niche for tumor colonization in the lung," Nature Communications, Nature, vol. 10(1), pages 1-16, December.
    6. Daniel S. Chen & Ira Mellman, 2017. "Elements of cancer immunity and the cancer–immune set point," Nature, Nature, vol. 541(7637), pages 321-330, January.
    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. Mike B. Barnkob & Yale S. Michaels & Violaine André & Philip S. Macklin & Uzi Gileadi & Salvatore Valvo & Margarida Rei & Corinna Kulicke & Ji-Li Chen & Vitul Jain & Victoria K. Woodcock & Huw Colin-Y, 2024. "Semaphorin 3A causes immune suppression by inducing cytoskeletal paralysis in tumour-specific CD8+ T cells," Nature Communications, Nature, vol. 15(1), pages 1-18, December.
    2. Feng Xie & Xiaoxue Zhou & Peng Su & Heyu Li & Yifei Tu & Jinjin Du & Chen Pan & Xiang Wei & Min Zheng & Ke Jin & Liyan Miao & Chao Wang & Xuli Meng & Hans Dam & Peter Dijke & Long Zhang & Fangfang Zho, 2022. "Breast cancer cell-derived extracellular vesicles promote CD8+ T cell exhaustion via TGF-β type II receptor signaling," Nature Communications, Nature, vol. 13(1), pages 1-18, December.
    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. Mengxue Zhou & Jiaxin Wang & Jiaxing Pan & Hui Wang & Lujia Huang & Bo Hou & Yi Lai & Fengyang Wang & Qingxiang Guan & Feng Wang & Zhiai Xu & Haijun Yu, 2023. "Nanovesicles loaded with a TGF-β receptor 1 inhibitor overcome immune resistance to potentiate cancer immunotherapy," Nature Communications, Nature, vol. 14(1), pages 1-18, December.
    5. Alessandra Castiglioni & Yagai Yang & Katherine Williams & Alvin Gogineni & Ryan S. Lane & Amber W. Wang & Justin A. Shyer & Zhe Zhang & Stephanie Mittman & Alan Gutierrez & Jillian L. Astarita & Minh, 2023. "Combined PD-L1/TGFβ blockade allows expansion and differentiation of stem cell-like CD8 T cells in immune excluded tumors," Nature Communications, Nature, vol. 14(1), pages 1-19, December.
    6. Maud Rijnders & J. Alberto Nakauma-González & Debbie G. J. Robbrecht & Alberto Gil-Jimenez & Hayri E. Balcioglu & Astrid A. M. Oostvogels & Maureen J. B. Aarts & Joost L. Boormans & Paul Hamberg & Mic, 2024. "Gene-expression-based T-Cell-to-Stroma Enrichment (TSE) score predicts response to immune checkpoint inhibitors in urothelial cancer," Nature Communications, Nature, vol. 15(1), pages 1-13, December.
    7. Jodi M. Carter & Saranya Chumsri & Douglas A. Hinerfeld & Yaohua Ma & Xue Wang & David Zahrieh & David W. Hillman & Kathleen S. Tenner & Jennifer M. Kachergus & Heather Ann Brauer & Sarah E. Warren & , 2023. "Distinct spatial immune microlandscapes are independently associated with outcomes in triple-negative breast cancer," Nature Communications, Nature, vol. 14(1), pages 1-14, December.
    8. Darci Phillips & Magdalena Matusiak & Belén Rivero Gutierrez & Salil S. Bhate & Graham L. Barlow & Sizun Jiang & Janos Demeter & Kimberly S. Smythe & Robert H. Pierce & Steven P. Fling & Nirasha Ramch, 2021. "Immune cell topography predicts response to PD-1 blockade in cutaneous T cell lymphoma," Nature Communications, Nature, vol. 12(1), pages 1-18, December.
    9. Stacy K. Thomas & Max M. Wattenberg & Shaanti Choi-Bose & Mark Uhlik & Ben Harrison & Heather Coho & Christopher R. Cassella & Meredith L. Stone & Dhruv Patel & Kelly Markowitz & Devora Delman & Micha, 2023. "Kupffer cells prevent pancreatic ductal adenocarcinoma metastasis to the liver in mice," Nature Communications, Nature, vol. 14(1), pages 1-17, December.
    10. Martin Lauss & Bengt Phung & Troels Holz Borch & Katja Harbst & Kamila Kaminska & Anna Ebbesson & Ingrid Hedenfalk & Joan Yuan & Kari Nielsen & Christian Ingvar & Ana Carneiro & Karolin Isaksson & Kri, 2024. "Molecular patterns of resistance to immune checkpoint blockade in melanoma," Nature Communications, Nature, vol. 15(1), pages 1-14, December.
    11. Alberto Gil-Jimenez & Nick Dijk & Joris L. Vos & Yoni Lubeck & Maurits L. Montfoort & Dennis Peters & Erik Hooijberg & Annegien Broeks & Charlotte L. Zuur & Bas W. G. Rhijn & Daniel J. Vis & Michiel S, 2024. "Spatial relationships in the urothelial and head and neck tumor microenvironment predict response to combination immune checkpoint inhibitors," Nature Communications, Nature, vol. 15(1), pages 1-15, December.
    12. Jeffrey S. Damrauer & Wolfgang Beckabir & Jeff Klomp & Mi Zhou & Elizabeth R. Plimack & Matthew D. Galsky & Petros Grivas & Noah M. Hahn & Peter H. O’Donnell & Gopa Iyer & David I. Quinn & Benjamin G., 2022. "Collaborative study from the Bladder Cancer Advocacy Network for the genomic analysis of metastatic urothelial cancer," Nature Communications, Nature, vol. 13(1), pages 1-15, December.
    13. Hong Yuen Wong & Quanhu Sheng & Amanda B. Hesterberg & Sarah Croessmann & Brenda L. Rios & Khem Giri & Jorgen Jackson & Adam X. Miranda & Evan Watkins & Kerry R. Schaffer & Meredith Donahue & Elizabet, 2022. "Single cell analysis of cribriform prostate cancer reveals cell intrinsic and tumor microenvironmental pathways of aggressive disease," Nature Communications, Nature, vol. 13(1), pages 1-21, December.
    14. Maria Pouyiourou & Bianca N. Kraft & Timothy Wohlfromm & Michael Stahl & Boris Kubuschok & Harald Löffler & Ulrich T. Hacker & Gerdt Hübner & Lena Weiss & Michael Bitzer & Thomas Ernst & Philipp Schüt, 2023. "Nivolumab and ipilimumab in recurrent or refractory cancer of unknown primary: a phase II trial," Nature Communications, Nature, vol. 14(1), pages 1-21, December.
    15. Aditi Sahu & Kivanc Kose & Lukas Kraehenbuehl & Candice Byers & Aliya Holland & Teguru Tembo & Anthony Santella & Anabel Alfonso & Madison Li & Miguel Cordova & Melissa Gill & Christi Fox & Salvador G, 2022. "In vivo tumor immune microenvironment phenotypes correlate with inflammation and vasculature to predict immunotherapy response," Nature Communications, Nature, vol. 13(1), pages 1-19, December.
    16. Maria Pia Lenza & Leire Egia-Mendikute & Asier Antoñana-Vildosola & Cátia O. Soares & Helena Coelho & Francisco Corzana & Alexandre Bosch & Prodhi Manisha & Jon Imanol Quintana & Iker Oyenarte & Luca , 2023. "Structural insights into Siglec-15 reveal glycosylation dependency for its interaction with T cells through integrin CD11b," Nature Communications, Nature, vol. 14(1), pages 1-14, December.
    17. Jia Wei & Xiaofeng Lu & Qin Liu & Yao Fu & Song Liu & Yang Zhao & Jiawei Zhou & Hui Chen & Meng Wang & Lin Li & Ju Yang & Fangcen Liu & Liming Zheng & Haitao Yin & Yang Yang & Chong Zhou & Ping Zeng &, 2023. "Neoadjuvant sintilimab in combination with concurrent chemoradiotherapy for locally advanced gastric or gastroesophageal junction adenocarcinoma: a single-arm phase 2 trial," Nature Communications, Nature, vol. 14(1), pages 1-12, December.
    18. Shaoshuai Tang & Yunzhi Wang & Rongkui Luo & Rundong Fang & Yufeng Liu & Hang Xiang & Peng Ran & Yexin Tong & Mingjun Sun & Subei Tan & Wen Huang & Jie Huang & Jiacheng Lv & Ning Xu & Zhenmei Yao & Qi, 2024. "Proteomic characterization identifies clinically relevant subgroups of soft tissue sarcoma," Nature Communications, Nature, vol. 15(1), pages 1-24, December.
    19. Alexandra Gyurdieva & Stefan Zajic & Ya-Fang Chang & E. Andres Houseman & Shan Zhong & Jaegil Kim & Michael Nathenson & Thomas Faitg & Mary Woessner & David C. Turner & Aisha N. Hasan & John Glod & Ro, 2022. "Biomarker correlates with response to NY-ESO-1 TCR T cells in patients with synovial sarcoma," Nature Communications, Nature, vol. 13(1), pages 1-18, December.
    20. E. H. Puttock & E. J. Tyler & M. Manni & E. Maniati & C. Butterworth & M. Burger Ramos & E. Peerani & P. Hirani & V. Gauthier & Y. Liu & G. Maniscalco & V. Rajeeve & P. Cutillas & C. Trevisan & M. Poz, 2023. "Extracellular matrix educates an immunoregulatory tumor macrophage phenotype found in ovarian cancer metastasis," Nature Communications, Nature, vol. 14(1), pages 1-16, 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_s41467-022-29026-9. 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.