(1) Herzog BH (2) Baer JM (3) Borcherding N (4) Kingston NL (5) Belle JI (6) Knolhoff BL (7) Hogg GD (8) Ahmad F (9) Kang LI (10) Petrone J (11) Lin CY (12) Govindan R (13) DeNardo DG
Herzog et al. studied the impact of fibrosis in the TME on NSCLC. In human NSCLC tissue, commonly observed fibrosis correlated with reduced CD8+ T cell infiltration, and in murine NSCLC models, induction of fibrosis led to increased tumor progression, decreased CD8+ T cells, and loss of response to anti-PD-1. Fibrosis caused functional changes in macrophages, DCs, and Col13+ CAFs that altered immune cell recruitment and enhanced TGFβ expression. Blocking TGFβR signaling in fibrosis models restored T cell responses and improved efficacy with chemotherapy/anti-PD-1, suggesting fibrosis could be targeted to overcome TME resistance.
Contributed by Katherine Turner
(1) Herzog BH (2) Baer JM (3) Borcherding N (4) Kingston NL (5) Belle JI (6) Knolhoff BL (7) Hogg GD (8) Ahmad F (9) Kang LI (10) Petrone J (11) Lin CY (12) Govindan R (13) DeNardo DG
Herzog et al. studied the impact of fibrosis in the TME on NSCLC. In human NSCLC tissue, commonly observed fibrosis correlated with reduced CD8+ T cell infiltration, and in murine NSCLC models, induction of fibrosis led to increased tumor progression, decreased CD8+ T cells, and loss of response to anti-PD-1. Fibrosis caused functional changes in macrophages, DCs, and Col13+ CAFs that altered immune cell recruitment and enhanced TGFβ expression. Blocking TGFβR signaling in fibrosis models restored T cell responses and improved efficacy with chemotherapy/anti-PD-1, suggesting fibrosis could be targeted to overcome TME resistance.
Contributed by Katherine Turner
Non-small cell lung cancer (NSCLC) is a leading cause of cancer-related deaths. Immune checkpoint blockade has improved survival for many patients with NSCLC, but most fail to obtain long-term benefit. Understanding the factors leading to reduced immune surveillance in NSCLC is critical in improving patient outcomes. Here, we show that human NSCLC harbors large amounts of fibrosis that correlates with reduced T cell infiltration. In murine NSCLC models, the induction of fibrosis led to increased lung cancer progression, impaired T cell immune surveillance, and failure of immune checkpoint blockade efficacy. Associated with these changes, we observed that fibrosis leads to numerically and functionally impaired dendritic cells and altered macrophage phenotypes that likely contribute to immunosuppression. Within cancer-associated fibroblasts, distinct changes within the Col13a1-expressing population suggest that these cells produce chemokines to recruit macrophages and regulatory T cells while limiting recruitment of dendritic cells and T cells. Targeting fibrosis through transforming growth factor-_ receptor signaling overcame the effects of fibrosis to enhance T cell responses and improved the efficacy of immune checkpoint blockade but only in the context of chemotherapy. Together, these data suggest that fibrosis in NSCLC leads to reduced immune surveillance and poor responsiveness to checkpoint blockade and highlight antifibrotic therapies as a candidate strategy to overcome immunotherapeutic resistance.
Author Info: (1) Department of Medicine, Washington University School of Medicine, St. Louis, MO 63110, USA. Siteman Cancer Center, Washington University School of Medicine, St. Louis, MO 63110
Author Info: (1) Department of Medicine, Washington University School of Medicine, St. Louis, MO 63110, USA. Siteman Cancer Center, Washington University School of Medicine, St. Louis, MO 63110, USA. (2) Department of Medicine, Washington University School of Medicine, St. Louis, MO 63110, USA. (3) Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO 63110, USA. (4) Department of Medicine, Washington University School of Medicine, St. Louis, MO 63110, USA. (5) Department of Medicine, Washington University School of Medicine, St. Louis, MO 63110, USA. (6) Department of Medicine, Washington University School of Medicine, St. Louis, MO 63110, USA. (7) Department of Medicine, Washington University School of Medicine, St. Louis, MO 63110, USA. (8) Department of Medicine, Washington University School of Medicine, St. Louis, MO 63110, USA. (9) Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO 63110, USA. (10) Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO 63110, USA. (11) Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO 63110, USA. (12) Department of Medicine, Washington University School of Medicine, St. Louis, MO 63110, USA. Siteman Cancer Center, Washington University School of Medicine, St. Louis, MO 63110, USA. (13) Siteman Cancer Center, Washington University School of Medicine, St. Louis, MO 63110, USA. Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO 63110, USA. Department of Surgery, Washington University School of Medicine, St. Louis, MO 63110, USA.
Citation: Sci Transl Med 2023 Jun 7 15:eadh8005 Epub06/07/2023
