To model tumor heterogeneity in prostate cancer, Tschering and Luo et al. used multicolor lineage tracing in GEMMs, and found that slow-growing tumors had a more evenly distributed multiclonal (“Mx”) tumor landscape, while more advanced or more aggressive tumors had fewer tumor clones, which were either dominant and minor (“D/M”), and a more disorganized immune landscape associated with differential editing. Minor clones were marked by increased IFNγ response genes, Cxcl9, Cxcl11, and MHC-II. IFNγ or Cxcl9 blockade stabilized the limited clonal dominance and rescued minor clones, which were associated with better outcomes in patients.
Contributed by Lauren Hitchings
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 IFN_-response genes and the T cell-activating chemokines Cxcl9 and Cxcl11. Furthermore, immunomodulation of the IFN_ 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.
Author Info: (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 Urolog
Author Info: (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 Urology, Stony Brook University, Stony Brook, NY 11794, USA; Department of Pathology, Stony Brook University, Stony Brook, NY 11794, USA. (3) Department of Urology, Stony Brook University, Stony Brook, NY 11794, USA; Department of Pathology, Stony Brook University, Stony Brook, NY 11794, USA. (4) 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. (5) Department of Urology, Stony Brook University, Stony Brook, NY 11794, USA; Department of Pathology, Stony Brook University, Stony Brook, NY 11794, USA. (6) Department of Urology, Stony Brook University, Stony Brook, NY 11794, USA; Department of Pathology, Stony Brook University, Stony Brook, NY 11794, USA. (7) Department of Urology, Stony Brook University, Stony Brook, NY 11794, USA; Department of Pathology, Stony Brook University, Stony Brook, NY 11794, USA. (8) 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. (9) 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. (10) 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.
