Using post-chemoembolization residual human hepatocellular carcinoma (HCC), Lemaitre, Adeniji, and Suresh et al. identified a spatial neighborhood of PD-L1+ M2-like macrophages and stem-like tumor cells that correlated with CD8+ T cell exhaustion and poor survival. Spatial transcriptomics showed that macrophage-derived TGFβ1 mediated the persistence of stem-like tumor cells. In a transgenic mouse model of HCC, recurrences arose from stem-like minimal residual disease. Combined blockade of PD-L1 and TGFβ excluded immunosuppressive macrophages, recruited activated CD8+ T cells, and eliminated residual stem-like tumor cells in mouse models of HCC.
Contributed by Shishir Pant
ABSTRACT: Hepatocellular carcinoma (HCC) frequently recurs from minimal residual disease (MRD), which persists after therapy. Here, we identified mechanisms of persistence of residual tumor cells using post-chemoembolization human HCC (n = 108 patients, 1.07 million cells) and a transgenic mouse model of MRD. Through single-cell high-plex cytometric imaging, we identified a spatial neighborhood within which PD-L1 + M2-like macrophages interact with stem-like tumor cells, correlating with CD8+ T cell exhaustion and poor survival. Further, through spatial transcriptomics of residual HCC, we showed that macrophage-derived TGFβ1 mediates the persistence of stem-like tumor cells. Last, we demonstrate that combined blockade of Pdl1 and Tgfβ excluded immunosuppressive macrophages, recruited activated CD8+ T cells and eliminated residual stem-like tumor cells in two mouse models: a transgenic model of MRD and a syngeneic orthotopic model of doxorubicin-resistant HCC. Thus, our spatial analyses reveal that PD-L1+ macrophages sustain MRD by activating the TGFβ pathway in stem-like cancer cells and targeting this interaction may prevent HCC recurrence from MRD.
Author Info: (1) Division of Gastroenterology and Hepatology, Stanford University, Stanford, CA, USA. (2) Division of Gastroenterology and Hepatology, Stanford University, Stanford, CA, USA. (3
Author Info: (1) Division of Gastroenterology and Hepatology, Stanford University, Stanford, CA, USA. (2) Division of Gastroenterology and Hepatology, Stanford University, Stanford, CA, USA. (3) Division of Gastroenterology and Hepatology, Stanford University, Stanford, CA, USA. (4) Division of Gastroenterology and Hepatology, Stanford University, Stanford, CA, USA. (5) Division of Gastroenterology and Hepatology, Stanford University, Stanford, CA, USA. (6) Division of Gastroenterology and Hepatology, Stanford University, Stanford, CA, USA. (7) Division of Gastroenterology and Hepatology, Stanford University, Stanford, CA, USA. (8) Enable Medicine, Menlo Park, CA, USA. (9) Enable Medicine, Menlo Park, CA, USA. (10) Division of Oncology, Departments of Medicine and Pathology, Stanford University, Stanford, CA, USA. (11) Department of Biomedicine, Aarhus University, Aarhus, Denmark. (12) Division of Oncology, Departments of Medicine and Pathology, Stanford University, Stanford, CA, USA. (13) Division of Gastroenterology and Hepatology, Stanford University, Stanford, CA, USA. (14) Department of Pathology, Stanford University, Stanford, CA, USA. (15) Department of Surgery, Stanford University, Stanford, CA, USA. (16) Department of Surgery, Stanford University, Stanford, CA, USA. (17) Department of Surgery, Stanford University, Stanford, CA, USA. (18) Department of Radiology, Stanford University, Stanford, CA, USA. (19) Enable Medicine, Menlo Park, CA, USA. (20) Enable Medicine, Menlo Park, CA, USA. (21) Department of Biomedical Data Science and Computer Science, Stanford University, Stanford, CA, USA. (22) Department of Biomedical Data Science and Computer Science, Stanford University, Stanford, CA, USA. (23) Department of Pathology, Stanford University, Stanford, CA, USA. (24) Division of Oncology, Departments of Medicine and Pathology, Stanford University, Stanford, CA, USA. dfelsher@stanford.edu. (25) Division of Gastroenterology and Hepatology, Stanford University, Stanford, CA, USA. dhanaser@stanford.edu.
