Lineage tracing reveals clonal progenitors and long-term persistence of tumor-specific T cells during immune checkpoint blockade

Joy A Pai; Matthew D Hellmann; Jennifer L Sauter; Marissa Mattar; Hira Rizvi; Hyung Jun Woo; Nisargbhai Shah; Evelyn M Nguyen; Fathema Z Uddin; Alvaro Quintanal-Villalonga; Joseph M Chan; Parvathy Manoj; Viola Allaj; Marina K Baine; Umesh K Bhanot; Mala Jain; Irina Linkov; Fanli Meng; David Brown; Jamie E Chaft; Andrew J Plodkowski; Mathieu Gigoux; Helen H Won; Triparna Sen; Daniel K Wells; Mark T A Donoghue; Elisa de Stanchina; Jedd D Wolchok; Brian Loomis; Taha Merghoub; Charles M Rudin; Andrew Chow; Ansuman T Satpathy

doi:10.1016/j.ccell.2023.03.009

Lineage tracing reveals clonal progenitors and long-term persistence of tumor-specific T cells during immune checkpoint blockade

Cancer Cell. 2023 Apr 10;41(4):776-790.e7. doi: 10.1016/j.ccell.2023.03.009. Epub 2023 Mar 30.

Authors

Joy A Pai¹, Matthew D Hellmann², Jennifer L Sauter³, Marissa Mattar⁴, Hira Rizvi⁵, Hyung Jun Woo⁶, Nisargbhai Shah⁷, Evelyn M Nguyen⁸, Fathema Z Uddin⁷, Alvaro Quintanal-Villalonga⁷, Joseph M Chan⁷, Parvathy Manoj⁷, Viola Allaj⁷, Marina K Baine³, Umesh K Bhanot⁹, Mala Jain⁹, Irina Linkov⁹, Fanli Meng⁶, David Brown⁶, Jamie E Chaft¹⁰, Andrew J Plodkowski¹¹, Mathieu Gigoux¹², Helen H Won⁶, Triparna Sen¹⁰, Daniel K Wells¹³, Mark T A Donoghue⁶, Elisa de Stanchina⁴, Jedd D Wolchok¹⁴, Brian Loomis⁶, Taha Merghoub¹⁴, Charles M Rudin¹⁵, Andrew Chow¹⁶, Ansuman T Satpathy¹⁷

Affiliations

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-Josée 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 Precision Pathology Center, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
¹⁰ Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA; Weill Cornell Medical College, New York, NY, USA.
¹¹ Department of Radiology, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
¹² Ludwig Collaborative and Swim Across America Laboratory, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
¹³ Parker Institute for Cancer Immunotherapy, San Francisco, CA, USA; Santa Ana Bio, Alameda, CA, USA.
¹⁴ 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.
¹⁵ 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.
¹⁶ 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: [email protected].
¹⁷ 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: [email protected].

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.

Keywords: TCF-1 progenitor exhausted T cells; exhausted T cells; immune checkpoint blockade; lung cancer; single-cell RNA/TCR sequencing; tumor-specific T cells.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

CD8-Positive T-Lymphocytes
Carcinoma, Non-Small-Cell Lung* / drug therapy
Clone Cells
Humans
Immune Checkpoint Inhibitors / therapeutic use
Lung Neoplasms* / drug therapy
Receptors, Antigen, T-Cell
Tumor Microenvironment

Substances

Immune Checkpoint Inhibitors
Receptors, Antigen, T-Cell

Abstract

Publication types

MeSH terms

Substances

Grants and funding