IDEAS home Printed from https://ideas.repec.org/a/nat/natcom/v15y2024i1d10.1038_s41467-024-49189-x.html
   My bibliography  Save this article

TSG-6+ cancer-associated fibroblasts modulate myeloid cell responses and impair anti-tumor response to immune checkpoint therapy in pancreatic cancer

Author

Listed:
  • Swetha Anandhan

    (The University of Texas MD Anderson Cancer Center
    The University of Texas MD Anderson Cancer Center
    The University of Texas MD Anderson Cancer Center)

  • Shelley Herbrich

    (The University of Texas MD Anderson Cancer Center
    The University of Texas MD Anderson Cancer Center)

  • Sangeeta Goswami

    (The University of Texas MD Anderson Cancer Center
    The University of Texas MD Anderson Cancer Center
    The University of Texas MD Anderson Cancer Center)

  • Baoxiang Guan

    (The University of Texas MD Anderson Cancer Center
    The University of Texas MD Anderson Cancer Center)

  • Yulong Chen

    (The University of Texas MD Anderson Cancer Center)

  • Marc Daniel Macaluso

    (The University of Texas MD Anderson Cancer Center)

  • Sonali Jindal

    (The University of Texas MD Anderson Cancer Center)

  • Seanu Meena Natarajan

    (The University of Texas MD Anderson Cancer Center)

  • Samuel W. Andrewes

    (The University of Texas MD Anderson Cancer Center
    The University of Texas MD Anderson Cancer Center
    The University of Texas MD Anderson Cancer Center)

  • Liangwen Xiong

    (The University of Texas MD Anderson Cancer Center
    The University of Texas MD Anderson Cancer Center)

  • Ashwat Nagarajan

    (The University of Texas MD Anderson Cancer Center
    The University of Texas MD Anderson Cancer Center)

  • Sreyashi Basu

    (The University of Texas MD Anderson Cancer Center)

  • Derek Ng Tang

    (The University of Texas MD Anderson Cancer Center
    The University of Texas MD Anderson Cancer Center)

  • Jielin Liu

    (The University of Texas MD Anderson Cancer Center
    The University of Texas MD Anderson Cancer Center
    The University of Texas MD Anderson Cancer Center)

  • Jimin Min

    (The University of Texas MD Anderson Cancer Center
    The University of Texas MD Anderson Cancer Center)

  • Anirban Maitra

    (The University of Texas MD Anderson Cancer Center
    The University of Texas MD Anderson Cancer Center)

  • Padmanee Sharma

    (The University of Texas MD Anderson Cancer Center
    The University of Texas MD Anderson Cancer Center
    The University of Texas MD Anderson Cancer Center
    The University of Texas MD Anderson Cancer Center)

Abstract

Resistance to immune checkpoint therapy (ICT) presents a growing clinical challenge. The tumor microenvironment (TME) and its components, namely tumor-associated macrophages (TAMs) and cancer-associated fibroblasts (CAFs), play a pivotal role in ICT resistance; however, the underlying mechanisms remain under investigation. In this study, we identify expression of TNF-Stimulated Factor 6 (TSG-6) in ICT-resistant pancreatic tumors, compared to ICT-sensitive melanoma tumors, both in mouse and human. TSG-6 is expressed by CAFs within the TME, where suppressive macrophages expressing Arg1, Mafb, and Mrc1, along with TSG-6 ligand Cd44, predominate. Furthermore, TSG-6 expressing CAFs co-localize with the CD44 expressing macrophages in the TME. TSG-6 inhibition in combination with ICT improves therapy response and survival in pancreatic tumor-bearing mice by reducing macrophages expressing immunosuppressive phenotypes and increasing CD8 T cells. Overall, our findings propose TSG-6 as a therapeutic target to enhance ICT response in non-responsive tumors.

Suggested Citation

  • Swetha Anandhan & Shelley Herbrich & Sangeeta Goswami & Baoxiang Guan & Yulong Chen & Marc Daniel Macaluso & Sonali Jindal & Seanu Meena Natarajan & Samuel W. Andrewes & Liangwen Xiong & Ashwat Nagara, 2024. "TSG-6+ cancer-associated fibroblasts modulate myeloid cell responses and impair anti-tumor response to immune checkpoint therapy in pancreatic cancer," Nature Communications, Nature, vol. 15(1), pages 1-13, December.
    • Handle: RePEc:nat:natcom:v:15:y:2024:i:1:d:10.1038_s41467-024-49189-x
    DOI: 10.1038/s41467-024-49189-x
    as

    Download full text from publisher

    File URL: https://www.nature.com/articles/s41467-024-49189-x
    File Function: Abstract
    Download Restriction: no
    File URL: https://libkey.io/10.1038/s41467-024-49189-x?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. Han Luo & Xuyang Xia & Li-Bin Huang & Hyunsu An & Minyuan Cao & Gyeong Dae Kim & Hai-Ning Chen & Wei-Han Zhang & Yang Shu & Xiangyu Kong & Zhixiang Ren & Pei-Heng Li & Yang Liu & Huairong Tang & Rongh, 2022. "Pan-cancer single-cell analysis reveals the heterogeneity and plasticity of cancer-associated fibroblasts in the tumor microenvironment," Nature Communications, Nature, vol. 13(1), pages 1-17, December.
    2. María Casanova-Acebes & Erica Dalla & Andrew M. Leader & Jessica LeBerichel & Jovan Nikolic & Blanca M. Morales & Markus Brown & Christie Chang & Leanna Troncoso & Steven T. Chen & Ana Sastre-Perona &, 2021. "Tissue-resident macrophages provide a pro-tumorigenic niche to early NSCLC cells," Nature, Nature, vol. 595(7868), pages 578-584, July.
    3. Akshay T. Krishnamurty & Justin A. Shyer & Minh Thai & Vineela Gandham & Matthew B. Buechler & Yeqing Angela Yang & Rachana N. Pradhan & Amber W. Wang & Patricia L. Sanchez & Yan Qu & Beatrice Breart , 2022. "LRRC15+ myofibroblasts dictate the stromal setpoint to suppress tumour immunity," Nature, Nature, vol. 611(7934), pages 148-154, November.
    4. Hao Chen & Mai Chan Lau & Michael Thomas Wong & Evan W Newell & Michael Poidinger & Jinmiao Chen, 2016. "Cytofkit: A Bioconductor Package for an Integrated Mass Cytometry Data Analysis Pipeline," PLOS Computational Biology, Public Library of Science, vol. 12(9), pages 1-17, September.
    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. Camille Cohen & Rana Mhaidly & Hugo Croizer & Yann Kieffer & Renaud Leclere & Anne Vincent-Salomon & Catherine Robley & Dany Anglicheau & Marion Rabant & Aurélie Sannier & Marc-Olivier Timsit & Sean E, 2024. "WNT-dependent interaction between inflammatory fibroblasts and FOLR2+ macrophages promotes fibrosis in chronic kidney disease," Nature Communications, Nature, vol. 15(1), pages 1-23, December.
    2. Daniel Haensel & Bence Daniel & Sadhana Gaddam & Cory Pan & Tania Fabo & Jeremy Bjelajac & Anna R. Jussila & Fernanda Gonzalez & Nancy Yanzhe Li & Yun Chen & JinChao Hou & Tiffany Patel & Sumaira Aasi, 2023. "Skin basal cell carcinomas assemble a pro-tumorigenic spatially organized and self-propagating Trem2+ myeloid niche," Nature Communications, Nature, vol. 14(1), pages 1-22, December.
    3. E. Koncina & M. Nurmik & V. I. Pozdeev & C. Gilson & M. Tsenkova & R. Begaj & S. Stang & A. Gaigneaux & C. Weindorfer & F. Rodriguez & M. Schmoetten & E. Klein & J. Karta & V. S. Atanasova & K. Grzyb , 2023. "IL1R1+ cancer-associated fibroblasts drive tumor development and immunosuppression in colorectal cancer," Nature Communications, Nature, vol. 14(1), pages 1-17, December.
    4. Junho Kang & Jun Hyeong Lee & Hongui Cha & Jinhyeon An & Joonha Kwon & Seongwoo Lee & Seongryong Kim & Mert Yakup Baykan & So Yeon Kim & Dohyeon An & Ah-Young Kwon & Hee Jung An & Se-Hoon Lee & Jung K, 2024. "Systematic dissection of tumor-normal single-cell ecosystems across a thousand tumors of 30 cancer types," Nature Communications, Nature, vol. 15(1), pages 1-17, December.
    5. Chih-Wei Chou & Chia-Nung Hung & Cheryl Hsiang-Ling Chiu & Xi Tan & Meizhen Chen & Chien-Chin Chen & Moawiz Saeed & Che-Wei Hsu & Michael A. Liss & Chiou-Miin Wang & Zhao Lai & Nathaniel Alvarez & Paw, 2023. "Phagocytosis-initiated tumor hybrid cells acquire a c-Myc-mediated quasi-polarization state for immunoevasion and distant dissemination," Nature Communications, Nature, vol. 14(1), pages 1-20, December.
    6. Víctor A. Arrieta & Andrew Gould & Kwang-Soo Kim & Karl J. Habashy & Crismita Dmello & Gustavo I. Vázquez-Cervantes & Irina Palacín-Aliana & Graysen McManus & Christina Amidei & Cristal Gomez & Silpol, 2024. "Ultrasound-mediated delivery of doxorubicin to the brain results in immune modulation and improved responses to PD-1 blockade in gliomas," Nature Communications, Nature, vol. 15(1), pages 1-19, December.
    7. Dehua Peng & Zhipeng Gui & Dehe Wang & Yuncheng Ma & Zichen Huang & Yu Zhou & Huayi Wu, 2022. "Clustering by measuring local direction centrality for data with heterogeneous density and weak connectivity," Nature Communications, Nature, vol. 13(1), pages 1-14, December.
    8. Ross J Burton & Raya Ahmed & Simone M Cuff & Sarah Baker & Andreas Artemiou & Matthias Eberl, 2021. "CytoPy: An autonomous cytometry analysis framework," PLOS Computational Biology, Public Library of Science, vol. 17(6), pages 1-21, June.
    9. Simone Puccio & Giorgio Grillo & Giorgia Alvisi & Caterina Scirgolea & Giovanni Galletti & Emilia Maria Cristina Mazza & Arianna Consiglio & Gabriele De Simone & Flavio Licciulli & Enrico Lugli, 2023. "CRUSTY: a versatile web platform for the rapid analysis and visualization of high-dimensional flow cytometry data," Nature Communications, Nature, vol. 14(1), pages 1-7, December.
    10. Chuan Shen & Yiyang Li & Boqian Wang & Zhipeng Zong & Tianfei Lu & Nokuzola Maboyi & Yuxiao Deng & Yongbing Qian & Jianjun Zhang & Xianting Ding & Qiang Xia, 2022. "HTLV-1 infection of donor-derived T cells might promote acute graft-versus-host disease following liver transplantation," Nature Communications, Nature, vol. 13(1), pages 1-12, December.
    11. Yongyao Fu & Abigail Pajulas & Jocelyn Wang & Baohua Zhou & Anthony Cannon & Cherry Cheuk Lam Cheung & Jilu Zhang & Huaxin Zhou & Amanda Jo Fisher & David T. Omstead & Sabrina Khan & Lei Han & Jean-Ch, 2022. "Mouse pulmonary interstitial macrophages mediate the pro-tumorigenic effects of IL-9," Nature Communications, Nature, vol. 13(1), pages 1-19, December.
    12. Luc Francis & Daniel McCluskey & Clarisse Ganier & Treasa Jiang & Xinyi Du-Harpur & Jeyrroy Gabriel & Pawan Dhami & Yogesh Kamra & Sudha Visvanathan & Jonathan N. Barker & Catherine H. Smith & Frances, 2024. "Single-cell analysis of psoriasis resolution demonstrates an inflammatory fibroblast state targeted by IL-23 blockade," Nature Communications, Nature, vol. 15(1), pages 1-14, December.
    13. Meirion Raymant & Yuliana Astuti & Laura Alvaro-Espinosa & Daniel Green & Valeria Quaranta & Gaia Bellomo & Mark Glenn & Vatshala Chandran-Gorner & Daniel H. Palmer & Christopher Halloran & Paula Ghan, 2024. "Macrophage-fibroblast JAK/STAT dependent crosstalk promotes liver metastatic outgrowth in pancreatic cancer," Nature Communications, Nature, vol. 15(1), pages 1-22, December.
    14. Alexander Coulton & Jun Murai & Danwen Qian & Krupa Thakkar & Claire E. Lewis & Kevin Litchfield, 2024. "Using a pan-cancer atlas to investigate tumour associated macrophages as regulators of immunotherapy response," Nature Communications, Nature, vol. 15(1), pages 1-14, December.
    15. Z. L. Liu & X. Y. Meng & R. J. Bao & M. Y. Shen & J. J. Sun & W. D. Chen & F. Liu & Y. He, 2024. "Single cell deciphering of progression trajectories of the tumor ecosystem in head and neck cancer," Nature Communications, Nature, vol. 15(1), pages 1-18, December.
    16. Zhaoqi Shu & Minghe Fan & Bo Tu & Zhiheng Tang & Haojie Wang & Haimeng Li & Hengchao Li & Meng Yuan & Jingru Bai & Sihan Huo & Lina Wang & Wei-Guo Zhu & Wei Wang & Xiaoyun Liu & Shaokun Shu & Ying Zha, 2023. "The Lin28b/Wnt5a axis drives pancreas cancer through crosstalk between cancer associated fibroblasts and tumor epithelium," Nature Communications, Nature, vol. 14(1), pages 1-18, December.
    17. Seiji Taniguchi & Takahiro Matsui & Kenji Kimura & Soichiro Funaki & Yu Miyamoto & Yutaka Uchida & Takao Sudo & Junichi Kikuta & Tetsuya Hara & Daisuke Motooka & Yu-Chen Liu & Daisuke Okuzaki & Eiichi, 2023. "In vivo induction of activin A-producing alveolar macrophages supports the progression of lung cell carcinoma," Nature Communications, Nature, vol. 14(1), pages 1-14, December.
    18. Eddie A. James & V. Michael Holers & Radhika Iyer & E. Barton Prideaux & Navin L. Rao & Cliff Rims & Virginia S. Muir & Sylvia E. Posso & Michelle S. Bloom & Amin Zia & Serra E. Elliott & Julia Z. Ada, 2023. "Multifaceted immune dysregulation characterizes individuals at-risk for rheumatoid arthritis," Nature Communications, Nature, vol. 14(1), pages 1-12, December.
    19. Lena Cords & Sandra Tietscher & Tobias Anzeneder & Claus Langwieder & Martin Rees & Natalie Souza & Bernd Bodenmiller, 2023. "Cancer-associated fibroblast classification in single-cell and spatial proteomics data," Nature Communications, Nature, vol. 14(1), pages 1-13, December.
    20. Yin Li & Manling Jiang & Ling Aye & Li Luo & Yong Zhang & Fengkai Xu & Yongqi Wei & Dan Peng & Xiang He & Jie Gu & Xiaofang Yu & Guoping Li & Di Ge & Chunlai Lu, 2024. "UPP1 promotes lung adenocarcinoma progression through the induction of an immunosuppressive microenvironment," Nature Communications, Nature, vol. 15(1), pages 1-23, 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:15:y:2024:i:1:d:10.1038_s41467-024-49189-x. 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.