TSG-6+ Cancer-Associated Fibroblasts Modulate Myeloid Cell Responses and Impair Anti-Tumor Response to Immune Checkpoint Therapy in Pancreatic Cancer

Authors

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
Padmanee Sharma

Publication Date

7-10-2024

Journal

Nature Communications

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.

Keywords

Animals, Pancreatic Neoplasms, Humans, Tumor Microenvironment, Cancer-Associated Fibroblasts, Mice, Immune Checkpoint Inhibitors, Cell Line, Tumor, Cell Adhesion Molecules, Myeloid Cells, Tumor-Associated Macrophages, Mice, Inbred C57BL, Female, Drug Resistance, Neoplasm, Macrophages, CD8-Positive T-Lymphocytes

Comments

Supplementary Materials

PMID: 38987547