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.
Developmental cell. 2023 May 05 [Epub]
Lara F Tshering, Fu Luo, Savanah Russ, Mariola Szenk, Diana Rubel, Karis Tutuska, James G Rail, Gábor Balázsi, Michael M Shen, Flaminia Talos
Department of Urology, Stony Brook University, Stony Brook, NY 11794, USA; Department of Pathology, Stony Brook University, Stony Brook, NY 11794, USA., 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., 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: ., 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: .