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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
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