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

Autor: Anandhan, Swetha, Herbrich, Shelley, Goswami, Sangeeta, Guan, Baoxiang, Chen, Yulong, Macaluso, Marc Daniel, Jindal, Sonali, Natarajan, Seanu Meena, Andrewes, Samuel W., Xiong, Liangwen, Nagarajan, Ashwat, Basu, Sreyashi, Tang, Derek Ng, Liu, Jielin, Min, Jimin, Maitra, Anirban, Sharma, Padmanee
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Zdroj: Nature Communications; 7/10/2024, Vol. 15 Issue 1, p1-13, 13p
Abstrakt: 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. Pancreatic ductal carcinoma (PDAC) is characterized by an immunosuppressive tumor microenvironment (TME) enriched in stromal cells. Here the authors show that TSG-6-positive cancer associated fibroblasts modulate myeloid cell responses and that TSG-6 targeting improves response to immune checkpoint inhibitors in preclinical PDAC models. [ABSTRACT FROM AUTHOR]
Databáze: Complementary Index
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