Using scRNA, transcriptome, and TCR analyses, Pauken et al. showed that blood CD8+ T cells expressing the same TCRs as CD8+ T cells in patients’ melanomas or in murine adenocarcinomas (‘tumor matching’; TM) were more activated/less exhausted Teff and TEM cells than matched intratumoral T cells or unmatched blood T cells. Transcriptome analyses identified and CITE-seq validated NKG2D, CD39 and CX3CR1 (but not PD-1) in mice as TM cell markers. Combining markers improved TM cell identification in mice and in patients with melanoma. TM cells shifted to a more exhausted profile in two longitudinal samples from two anti-PD-1-unresponsive patients with melanoma.
Contributed by Paula Hochman
ABSTRACT: The ability to monitor anti-tumor CD8+ T cell responses in the blood has tremendous therapeutic potential. Here, we used paired single-cell RNA and TCR sequencing to detect and characterize "tumor-matching" (TM) CD8+ T cells in the blood of mice with MC38 tumors or melanoma patients using the TCR as a molecular barcode. TM cells showed increased activation compared with nonmatching T cells in blood and were less exhausted than matching cells in tumors. Importantly, PD-1, which has been used to identify putative circulating anti-tumor CD8+ T cells, showed poor sensitivity for identifying TM cells. By leveraging the transcriptome, we identified candidate cell surface markers for TM cells in mice and patients and validated NKG2D, CD39, and CX3CR1 in mice. These data show that the TCR can be used to identify tumor-relevant cells for characterization, reveal unique transcriptional properties of TM cells, and develop marker panels for tracking and analysis of these cells.
Author Info: (1) Department of Immunology, Blavatnik Institute, Harvard Medical School, Boston, MA. Evergrande Center for Immunological Diseases, Harvard Medical School and Brigham and Women's
Author Info: (1) Department of Immunology, Blavatnik Institute, Harvard Medical School, Boston, MA. Evergrande Center for Immunological Diseases, Harvard Medical School and Brigham and Women's Hospital, Boston, MA. (2) Department of Data Sciences, Dana-Farber Cancer Institute, Boston, MA. (3) Department of Data Sciences, Dana-Farber Cancer Institute, Boston, MA. Harvard-MIT Medical Scientist Training Program, Harvard Medical School, Boston, MA. (4) Department of Surgery, University of California, San Francisco, San Francisco, CA. (5) Department of Data Sciences, Dana-Farber Cancer Institute, Boston, MA. Broad Institute of MIT and Harvard, Cambridge, MA. Department of Biomedical Informatics, Harvard Medical School, Boston, MA. (6) Department of Dermatology, University of California, San Francisco, San Francisco, CA. (7) Department of Data Sciences, Dana-Farber Cancer Institute, Boston, MA. Department of Biostatistics, Harvard H. Chan School of Public Health, Boston, MA. (8) Department of Data Sciences, Dana-Farber Cancer Institute, Boston, MA. (9) Department of Immunology, Blavatnik Institute, Harvard Medical School, Boston, MA. Evergrande Center for Immunological Diseases, Harvard Medical School and Brigham and Women's Hospital, Boston, MA. Department of Bioengineering, Northeastern University, Boston, MA. (10) Department of Data Sciences, Dana-Farber Cancer Institute, Boston, MA. (11) Department of Data Sciences, Dana-Farber Cancer Institute, Boston, MA. (12) Department of Medicine, University of California, San Francisco, San Francisco, CA. Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, San Francisco, CA. (13) Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, San Francisco, CA. (14) Department of Immunology, Blavatnik Institute, Harvard Medical School, Boston, MA. Evergrande Center for Immunological Diseases, Harvard Medical School and Brigham and Women's Hospital, Boston, MA. (15) Department of Immunology, Blavatnik Institute, Harvard Medical School, Boston, MA. Evergrande Center for Immunological Diseases, Harvard Medical School and Brigham and Women's Hospital, Boston, MA. (16) Department of Immunology, Blavatnik Institute, Harvard Medical School, Boston, MA. Evergrande Center for Immunological Diseases, Harvard Medical School and Brigham and Women's Hospital, Boston, MA. Department of Medical Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, MA. (17) Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA. Department of Pathology, Brigham and Women's Hospital, Boston, MA. (18) Department of Dermatology, University of California, San Francisco, San Francisco, CA. (19) Department of Medicine, University of California, San Francisco, San Francisco, CA. (20) Department of Immunology, Blavatnik Institute, Harvard Medical School, Boston, MA. Evergrande Center for Immunological Diseases, Harvard Medical School and Brigham and Women's Hospital, Boston, MA. Broad Institute of MIT and Harvard, Cambridge, MA. (21) Department of Immunology, Blavatnik Institute, Harvard Medical School, Boston, MA. Department of Data Sciences, Dana-Farber Cancer Institute, Boston, MA. Broad Institute of MIT and Harvard, Cambridge, MA.
