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

Autor:	Anandhan S; Department of Genitourinary Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.; The University of Texas MD Anderson Cancer Center UTHealth Houston Graduate School of Biomedical Sciences, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.; The James P. Allison Institute, The University of Texas MD Anderson Cancer Center, Houston, TX, USA., Herbrich S; Department of Genitourinary Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.; The James P. Allison Institute, The University of Texas MD Anderson Cancer Center, Houston, TX, USA., Goswami S; Department of Genitourinary Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.; The James P. Allison Institute, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.; Department of Immunology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA., Guan B; Department of Genitourinary Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.; The James P. Allison Institute, The University of Texas MD Anderson Cancer Center, Houston, TX, USA., Chen Y; Immunotherapy Platform, The University of Texas MD Anderson Cancer Center, Houston, TX, USA., Macaluso MD; Immunotherapy Platform, The University of Texas MD Anderson Cancer Center, Houston, TX, USA., Jindal S; Immunotherapy Platform, The University of Texas MD Anderson Cancer Center, Houston, TX, USA., Natarajan SM; Department of Immunology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA., Andrewes SW; Department of Genitourinary Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.; The University of Texas MD Anderson Cancer Center UTHealth Houston Graduate School of Biomedical Sciences, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.; The James P. Allison Institute, The University of Texas MD Anderson Cancer Center, Houston, TX, USA., Xiong L; Department of Genitourinary Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.; The James P. Allison Institute, The University of Texas MD Anderson Cancer Center, Houston, TX, USA., Nagarajan A; Department of Genitourinary Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.; The James P. Allison Institute, The University of Texas MD Anderson Cancer Center, Houston, TX, USA., Basu S; Immunotherapy Platform, The University of Texas MD Anderson Cancer Center, Houston, TX, USA., Tang DN; Department of Genitourinary Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.; The James P. Allison Institute, The University of Texas MD Anderson Cancer Center, Houston, TX, USA., Liu J; Department of Genitourinary Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.; The University of Texas MD Anderson Cancer Center UTHealth Houston Graduate School of Biomedical Sciences, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.; The James P. Allison Institute, The University of Texas MD Anderson Cancer Center, Houston, TX, USA., Min J; Department of Translational Molecular Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.; Sheikh Ahmed Center for Pancreatic Cancer Research, The University of Texas MD Anderson Cancer Center, Houston, TX, USA., Maitra A; Department of Translational Molecular Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.; Sheikh Ahmed Center for Pancreatic Cancer Research, The University of Texas MD Anderson Cancer Center, Houston, TX, USA., Sharma P; Department of Genitourinary Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA. PadSharma@mdanderson.org.; The James P. Allison Institute, The University of Texas MD Anderson Cancer Center, Houston, TX, USA. PadSharma@mdanderson.org.; Department of Immunology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA. PadSharma@mdanderson.org.; Immunotherapy Platform, The University of Texas MD Anderson Cancer Center, Houston, TX, USA. PadSharma@mdanderson.org.
Jazyk:	angličtina
Zdroj:	Nature communications [Nat Commun] 2024 Jul 10; Vol. 15 (1), pp. 5291. Date of Electronic Publication: 2024 Jul 10.
DOI:	10.1038/s41467-024-49189-x
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. (© 2024. The Author(s).)
Databáze:	MEDLINE
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