Spatial analysis reveals targetable macrophage-mediated mechanisms of immune evasion in hepatocellular carcinoma minimal residual disease
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<sup>+</sup> 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<sup>+</sup> 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<sup>+</sup> macrophages sustain MRD by activating the TGFβ pathway in stem-like cancer cells and targeting this interaction may prevent HCC recurrence from MRD.
Authors
- H. Blaize D’Angio (ORCID: https://orcid.org/0000-0001-8379-8123)
- James Zou (ORCID: https://orcid.org/0000-0001-8880-4764)
- Jangho Park (ORCID: https://orcid.org/0000-0002-6151-5193)
- Dean W. Felsher (ORCID: https://orcid.org/0000-0003-2496-523X)
- Clark A. Bonham (ORCID: https://orcid.org/0000-0002-7941-8607)
- Anja Deutzmann (ORCID: https://orcid.org/0000-0002-3271-1427)
- Aida S. Hansen (ORCID: https://orcid.org/0000-0002-6547-8393)
- Neeraja Kambham (ORCID: https://orcid.org/0000-0003-1136-3686)
- Monica M. Dua (ORCID: https://orcid.org/0000-0002-6187-8517)
- L Lemaître (ORCID: https://orcid.org/0000-0003-1940-1018)
- Vivek Charu (ORCID: https://orcid.org/0000-0002-7147-9026)
- Alexandro E. Trevino (ORCID: https://orcid.org/0000-0002-9763-1540)
- Yanay Rosen (ORCID: https://orcid.org/0000-0003-1129-9645)
- Aaron T. Mayer (ORCID: https://orcid.org/0000-0001-6429-0420)
- Renumathy Dhanasekaran (ORCID: https://orcid.org/0000-0001-8819-7511)
- Vinodhini Arjunan
- Ryan Preska
- Josephine Zhang (ORCID: https://orcid.org/0000-0001-6921-0944)
- Nia Adeniji (ORCID: https://orcid.org/0000-0002-7957-5987)
- Nishita Kothary (ORCID: https://orcid.org/0000-0002-9482-2077)
- Brendan C. Visser (ORCID: https://orcid.org/0000-0002-4874-1874)
- A.Krishna Reddy
- Akanksha Suresh (ORCID: https://orcid.org/0000-0002-3393-7495)
- Reshma Reguram (ORCID: https://orcid.org/0009-0003-5453-0082)
- Ling Tong (ORCID: https://orcid.org/0000-0003-4634-9462)
Institutions
- Aarhus University (DK)
- Menlo School (US)
- Stanford Medicine (US)
- Enable Biosciences (United States) (US)
- Stanford University (US)
Publication Details
- Journal
- Nature Cancer
- Published
- 2024-09-20
- DOI
- https://doi.org/10.1038/s43018-024-00828-8
- Citations
- 39
- Primary Topic
- Immune cells in cancer
- Type
- article
- Field-Weighted Citation Impact
- 9.38
Funders
- American College of Gastroenterology
- Center for Strategic Scientific Initiatives, National Cancer Institute