Pai et al. performed scRNA/TCRseq on T cells from three patients with non-small cell lung cancer (31 tissue regions, including tumors, adjacent normal tissues, and lymph nodes) to systematically profile the regional distribution, region-dependent cell states, and long-term persistence of tumor-specific T cells post ICB. Clonally expanded CD8+ T cells, Tregs, and follicular helper CD4+ T cells with tumor-specific features showed progressive exhaustion in proximity to viable cancer cells, and were clonally linked with TCF7+ progenitor exhausted T cells in lymph nodes. Tumor-specific T cell clones persisted in the blood for years after ICB therapy.
Contributed by Shishir Pant
ABSTRACT: Paired single-cell RNA and T cell receptor sequencing (scRNA/TCR-seq) has allowed for enhanced resolution of clonal T cell dynamics in cancer. Here, we report a scRNA/TCR-seq analysis of 187,650 T cells from 31 tissue regions, including tumor, adjacent normal tissues, and lymph nodes (LN), from three patients with non-small cell lung cancer after immune checkpoint blockade (ICB). Regions with viable cancer cells are enriched for exhausted CD8(+) T cells, regulatory CD4(+) T cells (Treg), and follicular helper CD4(+) T cells (TFH). Tracking T cell clonotypes across tissues, combined with neoantigen specificity assays, reveals that TFH and tumor-specific exhausted CD8(+) T cells are clonally linked to TCF7(+)SELL(+) progenitors in tumor draining LNs, and progressive exhaustion trajectories of CD8(+) T, Treg, and TFH cells with proximity to the tumor microenvironment. Finally, longitudinal tracking of tumor-specific CD8(+) and CD4(+) T cell clones reveals persistence in the peripheral blood for years after ICB therapy.
Author Info: (1) Department of Pathology, Stanford University, Stanford, CA, USA; Immunology Program, Stanford University, Stanford, CA, USA. (2) Department of Medicine, Memorial Sloan Ketterin
Author Info: (1) Department of Pathology, Stanford University, Stanford, CA, USA; Immunology Program, Stanford University, Stanford, CA, USA. (2) Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA; Weill Cornell Medical College, New York, NY, USA; Parker Institute for Cancer Immunotherapy, Memorial Sloan Kettering Cancer Center, New York, NY, USA. (3) Department of Pathology and Laboratory Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA. (4) Antitumor Assessment Core Facility, Memorial Sloan Kettering Cancer Center, New York, NY, USA. (5) Druckenmiller Center for Lung Cancer Research, Memorial Sloan Kettering Cancer Center, New York, NY, USA. (6) Marie-Jose and Henry R. Kravis Center for Molecular Oncology, Memorial Sloan Kettering Cancer Center, New York, NY, USA. (7) Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA. (8) Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA; Cancer Biology Program, Louis V. Gerstner Jr. Graduate School of Biomedical Sciences, Memorial Sloan Kettering Cancer Center, New York, NY, USA. (9) Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA. (10) Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA. (11) Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA. (12) Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA. (13) Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA. (14) Department of Pathology and Laboratory Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA. (15) Precision Pathology Center, Memorial Sloan Kettering Cancer Center, New York, NY, USA. (16) Precision Pathology Center, Memorial Sloan Kettering Cancer Center, New York, NY, USA. (17) Precision Pathology Center, Memorial Sloan Kettering Cancer Center, New York, NY, USA. (18) Marie-Jose and Henry R. Kravis Center for Molecular Oncology, Memorial Sloan Kettering Cancer Center, New York, NY, USA. (19) Marie-Jose and Henry R. Kravis Center for Molecular Oncology, Memorial Sloan Kettering Cancer Center, New York, NY, USA. (20) Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA; Weill Cornell Medical College, New York, NY, USA. (21) Department of Radiology, Memorial Sloan Kettering Cancer Center, New York, NY, USA. (22) Ludwig Collaborative and Swim Across America Laboratory, Memorial Sloan Kettering Cancer Center, New York, NY, USA. (23) Marie-Jose and Henry R. Kravis Center for Molecular Oncology, Memorial Sloan Kettering Cancer Center, New York, NY, USA. (24) Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA; Weill Cornell Medical College, New York, NY, USA. (25) Parker Institute for Cancer Immunotherapy, San Francisco, CA, USA; Santa Ana Bio, Alameda, CA, USA. (26) Marie-Jose and Henry R. Kravis Center for Molecular Oncology, Memorial Sloan Kettering Cancer Center, New York, NY, USA. (27) Antitumor Assessment Core Facility, Memorial Sloan Kettering Cancer Center, New York, NY, USA. (28) Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA; Weill Cornell Medical College, New York, NY, USA; Parker Institute for Cancer Immunotherapy, Memorial Sloan Kettering Cancer Center, New York, NY, USA; Ludwig Collaborative and Swim Across America Laboratory, Memorial Sloan Kettering Cancer Center, New York, NY, USA; Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, NY, USA. (29) Marie-Jose and Henry R. Kravis Center for Molecular Oncology, Memorial Sloan Kettering Cancer Center, New York, NY, USA. (30) Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA; Weill Cornell Medical College, New York, NY, USA; Parker Institute for Cancer Immunotherapy, Memorial Sloan Kettering Cancer Center, New York, NY, USA; Ludwig Collaborative and Swim Across America Laboratory, Memorial Sloan Kettering Cancer Center, New York, NY, USA; Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, NY, USA. (31) Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA; Weill Cornell Medical College, New York, NY, USA; Druckenmiller Center for Lung Cancer Research, Memorial Sloan Kettering Cancer Center, New York, NY, USA. (32) Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA; Weill Cornell Medical College, New York, NY, USA; Ludwig Collaborative and Swim Across America Laboratory, Memorial Sloan Kettering Cancer Center, New York, NY, USA. Electronic address: chowa1@mskcc.org. (33) Department of Pathology, Stanford University, Stanford, CA, USA; Immunology Program, Stanford University, Stanford, CA, USA; Gladstone-UCSF Institute of Genomic Immunology, San Francisco, CA, USA; Stanford Cancer Institute, Stanford University, Stanford, CA, USA; Parker Institute for Cancer Immunotherapy, Stanford University, Stanford, CA, USA. Electronic address: satpathy@stanford.edu.
