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LRRC15+ myofibroblasts dictate the stromal setpoint to suppress tumour immunity

Author

Listed:
  • Akshay T. Krishnamurty

    (Genentech)

  • Justin A. Shyer

    (Genentech)

  • Minh Thai

    (Genentech)

  • Vineela Gandham

    (Genentech)

  • Matthew B. Buechler

    (Genentech)

  • Yeqing Angela Yang

    (Genentech)

  • Rachana N. Pradhan

    (Genentech)

  • Amber W. Wang

    (Genentech)

  • Patricia L. Sanchez

    (Genentech)

  • Yan Qu

    (Genentech)

  • Beatrice Breart

    (Genentech)

  • Cécile Chalouni

    (Genentech)

  • Debra Dunlap

    (Genentech)

  • James Ziai

    (Genentech)

  • Justin Elstrott

    (Genentech)

  • Neelie Zacharias

    (Genentech)

  • Weiguang Mao

    (Genentech)

  • Rebecca K. Rowntree

    (Genentech)

  • Jack Sadowsky

    (Genentech)

  • Gail D. Lewis

    (Genentech)

  • Thomas H. Pillow

    (Genentech)

  • Barzin Y. Nabet

    (Genentech)

  • Romain Banchereau

    (Genentech)

  • Lucinda Tam

    (Genentech)

  • Roger Caothien

    (Genentech)

  • Natasha Bacarro

    (Genentech)

  • Merone Roose-Girma

    (Genentech)

  • Zora Modrusan

    (Genentech)

  • Sanjeev Mariathasan

    (Genentech)

  • Sören Müller

    (Genentech)

  • Shannon J. Turley

    (Genentech)

Abstract

Recent single-cell studies of cancer in both mice and humans have identified the emergence of a myofibroblast population specifically marked by the highly restricted leucine-rich-repeat-containing protein 15 (LRRC15)1–3. However, the molecular signals that underlie the development of LRRC15+ cancer-associated fibroblasts (CAFs) and their direct impact on anti-tumour immunity are uncharacterized. Here in mouse models of pancreatic cancer, we provide in vivo genetic evidence that TGFβ receptor type 2 signalling in healthy dermatopontin+ universal fibroblasts is essential for the development of cancer-associated LRRC15+ myofibroblasts. This axis also predominantly drives fibroblast lineage diversity in human cancers. Using newly developed Lrrc15–diphtheria toxin receptor knock-in mice to selectively deplete LRRC15+ CAFs, we show that depletion of this population markedly reduces the total tumour fibroblast content. Moreover, the CAF composition is recalibrated towards universal fibroblasts. This relieves direct suppression of tumour-infiltrating CD8+ T cells to enhance their effector function and augments tumour regression in response to anti-PDL1 immune checkpoint blockade. Collectively, these findings demonstrate that TGFβ-dependent LRRC15+ CAFs dictate the tumour-fibroblast setpoint to promote tumour growth. These cells also directly suppress CD8+ T cell function and limit responsiveness to checkpoint blockade. Development of treatments that restore the homeostatic fibroblast setpoint by reducing the population of pro-disease LRRC15+ myofibroblasts may improve patient survival and response to immunotherapy.

Suggested Citation

  • 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.
  • Handle: RePEc:nat:nature:v:611:y:2022:i:7934:d:10.1038_s41586-022-05272-1
    DOI: 10.1038/s41586-022-05272-1
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    Cited by:

    1. 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.
    2. 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.
    3. Hugo Croizer & Rana Mhaidly & Yann Kieffer & Geraldine Gentric & Lounes Djerroudi & Renaud Leclere & Floriane Pelon & Catherine Robley & Mylene Bohec & Arnaud Meng & Didier Meseure & Emanuela Romano &, 2024. "Deciphering the spatial landscape and plasticity of immunosuppressive fibroblasts in breast cancer," Nature Communications, Nature, vol. 15(1), pages 1-28, December.
    4. Marina T. Broz & Emily Y. Ko & Kristin Ishaya & Jinfen Xiao & Marco Simone & Xen Ping Hoi & Roberta Piras & Basia Gala & Fernando H. G. Tessaro & Anja Karlstaedt & Sandra Orsulic & Amanda W. Lund & Ke, 2024. "Metabolic targeting of cancer associated fibroblasts overcomes T-cell exclusion and chemoresistance in soft-tissue sarcomas," Nature Communications, Nature, vol. 15(1), pages 1-18, December.
    5. 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.
    6. 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.
    7. Gaoyang Liang & Tae Gyu Oh & Nasun Hah & Hervé Tiriac & Yu Shi & Morgan L. Truitt & Corina E. Antal & Annette R. Atkins & Yuwenbin Li & Cory Fraser & Serina Ng & Antonio F. M. Pinto & Dylan C. Nelson , 2023. "Inhibiting stromal Class I HDACs curbs pancreatic cancer progression," Nature Communications, Nature, vol. 14(1), pages 1-18, December.
    8. Monika Licaj & Rana Mhaidly & Yann Kieffer & Hugo Croizer & Claire Bonneau & Arnaud Meng & Lounes Djerroudi & Kevin Mujangi-Ebeka & Hocine R. Hocine & Brigitte Bourachot & Ilaria Magagna & Renaud Lecl, 2024. "Residual ANTXR1+ myofibroblasts after chemotherapy inhibit anti-tumor immunity via YAP1 signaling pathway," Nature Communications, Nature, vol. 15(1), pages 1-27, December.
    9. 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.

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