Journal article
Progressive immune dysfunction with advancing disease stage in renal cell carcinoma
Dana-Farber Cancer Institute1
Massachusetts General Hospital/Harvard Medical School2
McLean Hospital3
Single Cell Omics, Bioinformatics, Department of Health Technology, Technical University of Denmark4
Bioinformatics, Department of Health Technology, Technical University of Denmark5
Department of Health Technology, Technical University of Denmark6
University College Hospital London7
Broad Institute of Harvard University and Massachusetts Institute of Technology8
The tumor immune microenvironment plays a critical role in cancer progression and response to immunotherapy in clear cell renal cell carcinoma (ccRCC), yet the composition and phenotypic states of immune cells in this tumor are incompletely characterized. We performed single-cell RNA and T cell receptor sequencing on 164,722 individual cells from tumor and adjacent non-tumor tissue in patients with ccRCC across disease stages: early, locally advanced, and advanced/metastatic.
Terminally exhausted CD8+ T cells were enriched in metastatic disease and were restricted in T cell receptor diversity. Within the myeloid compartment, pro-inflammatory macrophages were decreased, and suppressive M2-like macrophages were increased in advanced disease. Terminally exhausted CD8+ T cells and M2-like macrophages co-occurred in advanced disease and expressed ligands and receptors that support T cell dysfunction and M2-like polarization.
This immune dysfunction circuit is associated with a worse prognosis in external cohorts and identifies potentially targetable immune inhibitory pathways in ccRCC.
Language: | English |
---|---|
Year: | 2021 |
Pages: | 632-648 |
ISSN: | 15356108 and 18783686 |
Types: | Journal article |
DOI: | 10.1016/j.ccell.2021.02.013 |
ORCIDs: | 0000-0003-4543-5553 , 0000-0001-6379-5013 , 0000-0003-2187-0147 , 0000-0002-8618-7691 , Pedersen, Christina B. , 0000-0003-2277-7729 , 0000-0003-1906-5704 , 0000-0002-4377-4204 , 0000-0002-1087-8568 , 0000-0002-8450-2037 , 0000-0002-3869-6803 , 0000-0002-8298-0289 , 0000-0002-8767-8564 , 0000-0001-9105-5856 , Olsen, Lars R. , 0000-0002-5000-9105 and 0000-0002-9201-3217 |
Biomarkers, Tumor CD8 T cell exhaustion CD8-Positive T-Lymphocytes Carcinoma, Renal Cell Gene Expression Regulation, Neoplastic Humans Immunotherapy Kidney Neoplasms Lymphocytes, Tumor-Infiltrating Macrophages Tumor Microenvironment cancer immunotherapy cell-cell interaction clear cell renal cell carcinoma immune cell atlas single-cell RNA sequencing tumor-associated macrophages