2. Academic Validation
  3. Immune mechanisms shape the clonal landscape during early progression of prostate cancer

Immune mechanisms shape the clonal landscape during early progression of prostate cancer

  • Dev Cell. 2023 Jun 19;58(12):1071-1086.e8. doi: 10.1016/j.devcel.2023.04.010.
Lara F Tshering 1,  Fu Luo 1,  Savanah Russ 1,  Mariola Szenk 2,  Diana Rubel 1,  Karis Tutuska 1,  James G Rail 1,  Gábor Balázsi 2,  Michael M Shen 3,  Flaminia Talos 4
Affiliations

Affiliations

  • 1 Department of Urology, Stony Brook University, Stony Brook, NY 11794, USA; Department of Pathology, Stony Brook University, Stony Brook, NY 11794, USA.
  • 2 Department of Biomedical Engineering, Stony Brook University, Stony Brook, NY 11794, USA; Laufer Center for Physical and Quantitative Biology, Stony Brook University, Stony Brook, NY 11794, USA.
  • 3 Departments of Medicine, Genetics & Development, Urology, and Systems Biology, Herbert Irving Comprehensive Cancer Center, Columbia University Irving Medical Center, New York, NY 10032, USA. Electronic address: mshen@columbia.edu.
  • 4 Department of Urology, Stony Brook University, Stony Brook, NY 11794, USA; Department of Pathology, Stony Brook University, Stony Brook, NY 11794, USA; Departments of Medicine, Genetics & Development, Urology, and Systems Biology, Herbert Irving Comprehensive Cancer Center, Columbia University Irving Medical Center, New York, NY 10032, USA; Stony Brook Cancer Center, Stony Brook University, Stony Brook, NY 11794, USA. Electronic address: flaminia.talos@stonybrookmedicine.edu.
PMID: 37148881 DOI: 10.1016/j.devcel.2023.04.010
Abstract

Understanding the role of the immune microenvironment in modulating intratumor heterogeneity is essential for effective Cancer therapies. Using multicolor lineage tracing in genetically engineered mouse models and single-cell transcriptomics, we show that slowly progressing tumors contain a multiclonal landscape of relatively homogeneous subpopulations within a well-organized tumor microenvironment. In more advanced and aggressive tumors, however, the multiclonal landscape develops into competing dominant and minor clones accompanied by a disordered microenvironment. We demonstrate that this dominant/minor landscape is associated with differential immunoediting, in which minor clones are marked by an increased expression of IFNγ-response genes and the T cell-activating chemokines CXCL9 and Cxcl11. Furthermore, immunomodulation of the IFNγ pathway can rescue minor clones from elimination. Notably, the immune-specific gene signature of minor clones exhibits a prognostic value for biochemical recurrence-free survival in human prostate Cancer. These findings suggest new immunotherapy approaches for modulating clonal fitness and tumor progression in prostate Cancer.

Keywords

clonal competition; immunoediting; prostate cancer; single-cell transcriptomics.

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