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Peer-reviewedCC BYCancer Cell

Clonal lineage tracing of innate immune cells in human cancer

  • Vincent Liu1,2
  • Katalin D. Sandor3,4
  • Patrick Yan3,4
  • Zhuang Miao5,2
  • Yajie Yin3,4
  • Robert R. Stickels3,4
  • Andy Y. Chen6,7
  • Kamir J. Hiam-Galvez3,4
  • Jacob C. Gutierrez8,9
  • Wenxi Zhang3,4
  • Sairaj M. Sajjath10,11
  • Raeline Valbuena12,2
6 more authors
  • Steven Wang12,2
  • Bence Dániel3,13
  • Leif S. Ludwig14,15,16
  • Brooke E. Howitt17,4
  • Caleb A. Lareau18,9
  • Ansuman T. Satpathy19,4,20
20 affiliations
  1. 1Department of Genetics, Stanford University, Stanford, CA 94305, USA; Department of Pathology, Stanford University, Stanford, CA 94305, USA; Center for Immunotherapy Design, Stanford University, Stanford, CA 94305, USA. Electronic address: [email protected]
  2. 2Department of Genetics, Stanford University, Stanford, CA, USA
  3. 3Department of Pathology, Stanford University, Stanford, CA 94305, USA; Center for Immunotherapy Design, Stanford University, Stanford, CA 94305, USA
  4. 4Department of Pathology, Stanford University, Stanford, CA, USA
  5. 5Department of Genetics, Stanford University, Stanford, CA 94305, USA; Department of Pathology, Stanford University, Stanford, CA 94305, USA; Center for Immunotherapy Design, Stanford University, Stanford, CA 94305, USA
  6. 6Department of Pathology, Stanford University, Stanford, CA 94305, USA; Center for Immunotherapy Design, Stanford University, Stanford, CA 94305, USA; Department of Bioengineering, Stanford University, Stanford, CA 94305, USA
  7. 7Department of Bioengineering, Stanford University, Stanford, CA, USA
  8. 8Computational and Systems Biology Program, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA
  9. 9Computational and Systems Biology Program, Memorial Sloan Kettering Cancer Center, New York, NY, USA
  10. 10Robin Chemers Neustein Laboratory of Mammalian Cell Biology and Development, Howard Hughes Medical Institute, The Rockefeller University, New York, NY 10065, USA
  11. 11Robin Chemers Neustein Laboratory of Mammalian Cell Biology and Development, Howard Hughes Medical Institute, The Rockefeller University, New York, NY 1005, USA
  12. 12Department of Genetics, Stanford University, Stanford, CA 94305, USA
  13. 13Center for Immunotherapy Design, Stanford University, Stanford, CA, USA
  14. 14Berlin Institute of Health at Charité - Universitätsmedizin Berlin, 10178 Berlin, Germany; Max-Delbrück-Center for Molecular Medicine in the Helmholtz Association (MDC) Berlin Institute for Medical Systems Biology (BIMSB), 10115 Berlin, Germany
  15. 15Berlin Institute of Health at Charité – Universitätsmedizin Berlin, Berlin, Germany
  16. 16Max-Delbrück-Center for Molecular Medicine in the Helmholtz Association (MDC) Berlin Institute for Medical Systems Biology (BIMSB), Berlin, Germany
  17. 17Department of Pathology, Stanford University, Stanford, CA 94305, USA
  18. 18Computational and Systems Biology Program, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA. Electronic address: [email protected]
  19. 19Department of Pathology, Stanford University, Stanford, CA 94305, USA; Center for Immunotherapy Design, Stanford University, Stanford, CA 94305, USA; Parker Institute for Cancer Immunotherapy, San Francisco, CA 94129, USA. Electronic address: [email protected]
  20. 20Parker Institute for Cancer Immunotherapy, San Francisco, CA, USA
Open at sourceDOICite

Abstract

Innate immune cells constitute the majority of the tumor microenvironment (TME), where they mediate both natural anti-tumor immunity and immunotherapy responses. While single-cell T- and B-cell receptor sequencing has provided fundamental insights into the clonal dynamics of human adaptive immunity, the lack of appropriate tools has precluded similar analysis of innate immune cells. Here, we describe a method that leverages somatic mitochondrial DNA (mtDNA) mutations to reconstruct clonal lineage relationships between single cells across cell types in native human tissues. We jointly sequenced single-cell transposase-accessible chromatin and mtDNA to profile n =124,958 cells from matched tumor, non-involved lung tissue (NILT), and peripheral blood of early-stage non-small cell lung cancer (NSCLC) patients, as well as n =93,757 cells from matched tumor and peripheral blood of ovarian cancer patients. Single-cell concomitant profiling of lineage and cell states of thousands of immune cells resolved clonality across cell types, tissue sites, and malignancies. Clonal tracing of innate immune cells demonstrates that TME-resident myeloid subsets, including macrophages and type 3 dendritic cells (DC3), are clonally linked to both circulating and tissue-infiltrating monocytes. Further, we identify distinct DC-biased and macrophage-biased myeloid clones, enriched in the tumor and NILT, respectively, and find that their circulating monocyte precursors exhibit distinct epigenetic profiles, suggesting that myeloid differentiation fate may be predetermined before TME infiltration. These results delineate the clonal pathways of intratumoral myeloid cell recruitment and differentiation in human cancer and suggest that remodeling of the tumor myeloid compartment may be peripherally programmed.

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Cite

BibTeXRIS
BibTeX
@article{liu2026clonal,
  title = {{Clonal lineage tracing of innate immune cells in human cancer}},
  author = {Vincent Liu and Katalin D. Sandor and Patrick Yan and Zhuang Miao and Yajie Yin and Robert R. Stickels and Andy Y. Chen and Kamir J. Hiam-Galvez and Jacob C. Gutierrez and Wenxi Zhang and Sairaj M. Sajjath and Raeline Valbuena and Steven Wang and Bence Dániel and Leif S. Ludwig and Brooke E. Howitt and Caleb A. Lareau and Ansuman T. Satpathy},
  journal = {Cancer Cell},
  year = {2026},
  month = jun,
  doi = {10.1016/j.ccell.2026.05.006},
  url = {https://doi.org/10.1016/j.ccell.2026.05.006},
  note = {CC BY},
}
RIS
TY  - JOUR
TI  - Clonal lineage tracing of innate immune cells in human cancer
AU  - Vincent Liu
AU  - Katalin D. Sandor
AU  - Patrick Yan
AU  - Zhuang Miao
AU  - Yajie Yin
AU  - Robert R. Stickels
AU  - Andy Y. Chen
AU  - Kamir J. Hiam-Galvez
AU  - Jacob C. Gutierrez
AU  - Wenxi Zhang
AU  - Sairaj M. Sajjath
AU  - Raeline Valbuena
AU  - Steven Wang
AU  - Bence Dániel
AU  - Leif S. Ludwig
AU  - Brooke E. Howitt
AU  - Caleb A. Lareau
AU  - Ansuman T. Satpathy
PY  - 2026
DA  - 2026/06/04
JO  - Cancer Cell
DO  - 10.1016/j.ccell.2026.05.006
UR  - https://doi.org/10.1016/j.ccell.2026.05.006
AB  - Innate immune cells constitute the majority of the tumor microenvironment (TME), where they mediate both natural anti-tumor immunity and immunotherapy responses. While single-cell T- and B-cell receptor sequencing has provided fundamental insights into the clonal dynamics of human adaptive immunity, the lack of appropriate tools has precluded similar analysis of innate immune cells. Here, we describe a method that leverages somatic mitochondrial DNA (mtDNA) mutations to reconstruct clonal lineage relationships between single cells across cell types in native human tissues. We jointly sequenced single-cell transposase-accessible chromatin and mtDNA to profile n =124,958 cells from matched tumor, non-involved lung tissue (NILT), and peripheral blood of early-stage non-small cell lung cancer (NSCLC) patients, as well as n =93,757 cells from matched tumor and peripheral blood of ovarian cancer patients. Single-cell concomitant profiling of lineage and cell states of thousands of immune cells resolved clonality across cell types, tissue sites, and malignancies. Clonal tracing of innate immune cells demonstrates that TME-resident myeloid subsets, including macrophages and type 3 dendritic cells (DC3), are clonally linked to both circulating and tissue-infiltrating monocytes. Further, we identify distinct DC-biased and macrophage-biased myeloid clones, enriched in the tumor and NILT, respectively, and find that their circulating monocyte precursors exhibit distinct epigenetic profiles, suggesting that myeloid differentiation fate may be predetermined before TME infiltration. These results delineate the clonal pathways of intratumoral myeloid cell recruitment and differentiation in human cancer and suggest that remodeling of the tumor myeloid compartment may be peripherally programmed.
SN  - 1535-6108
SN  - 1878-3686
ER  -