Anandhan et al. showed that the TME in mouse models of ICB-responsive pancreatic cancer, but not ICB-resistant melanoma, exhibited elevated levels of cancer-associated fibroblasts and the CAF-secreted myeloid regulator TNF-stimulated gene 6 (TSG-6). TSG-6 was also upregulated in human pancreatic tumors as compared to melanomas. In pancreatic tumors, TSG-6 co-localized with its ligand, CD44, on suppressive macrophages. In a mouse pancreatic tumor model, a trio of anti-TSG-6, anti-CTLA-4, and anti-PD-1 antibodies decreased TME levels of suppressive macrophages and Tregs, increased CD8+ T cells, and extended survival.
Contributed by Paula Hochman
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.
Author Info: (1) 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 Ho
Author Info: (1) 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. (2) 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. (3) 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. (4) 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. (5) Immunotherapy Platform, The University of Texas MD Anderson Cancer Center, Houston, TX, USA. (6) Immunotherapy Platform, The University of Texas MD Anderson Cancer Center, Houston, TX, USA. (7) Immunotherapy Platform, The University of Texas MD Anderson Cancer Center, Houston, TX, USA. (8) Department of Immunology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA. (9) 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. (10) 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. (11) 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. (12) Immunotherapy Platform, The University of Texas MD Anderson Cancer Center, Houston, TX, USA. (13) 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. (14) 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. (15) 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. (16) 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. (17) 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.
