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

Swetha Anandhan, Shelley Herbrich, Sangeeta Goswami, Baoxiang Guan, Yulong Chen, Marc Daniel Macaluso, Sonali Jindal, Seanu Meena Natarajan, Samuel W. Andrewes, Liangwen Xiong, Ashwat Nagarajan, Sreyashi Basu, Derek Ng Tang, Jielin Liu, Jimin Min, Anirban Maitra and Padmanee Sharma ()
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Swetha Anandhan: The University of Texas MD Anderson Cancer Center
Shelley Herbrich: The University of Texas MD Anderson Cancer Center
Sangeeta Goswami: The University of Texas MD Anderson Cancer Center
Baoxiang Guan: 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
Liangwen Xiong: The University of Texas MD Anderson Cancer Center
Ashwat Nagarajan: 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
Jielin Liu: The University of Texas MD Anderson Cancer Center
Jimin Min: The University of Texas MD Anderson Cancer Center
Anirban Maitra: The University of Texas MD Anderson Cancer Center
Padmanee Sharma: The University of Texas MD Anderson Cancer Center

Nature Communications, 2024, vol. 15, issue 1, 1-13

Abstract: 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.

Date: 2024
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DOI: 10.1038/s41467-024-49189-x

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