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

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

Research output: Contribution to journal › Article › peer-review

111 Scopus citations

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.

Original language	English
Pages (from-to)	776-790.e7
Journal	Cancer Cell
Volume	41
Issue number	4
DOIs	https://doi.org/10.1016/j.ccell.2023.03.009
State	Published - 10 Apr 2023
Externally published	Yes

Keywords

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

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10.1016/j.ccell.2023.03.009

Cite this

Pai, J. A., Hellmann, M. D., Sauter, J. L., Mattar, M., Rizvi, H., Woo, H. J., Shah, N., Nguyen, E. M., Uddin, F. Z., Quintanal-Villalonga, A., Chan, J. M., Manoj, P., Allaj, V., Baine, M. K., Bhanot, U. K., Jain, M., Linkov, I., Meng, F., Brown, D., ... Satpathy, A. T. (2023). Lineage tracing reveals clonal progenitors and long-term persistence of tumor-specific T cells during immune checkpoint blockade. Cancer Cell, 41(4), 776-790.e7. https://doi.org/10.1016/j.ccell.2023.03.009

@article{d6120f658aa34694a76a0a5dd395eba4,

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

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",

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

note = "Publisher Copyright: {\textcopyright} 2023 Elsevier Inc.",

year = "2023",

month = apr,

day = "10",

doi = "10.1016/j.ccell.2023.03.009",

language = "English",

volume = "41",

pages = "776--790.e7",

journal = "Cancer Cell",

issn = "1535-6108",

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Pai, JA, Hellmann, MD, Sauter, JL, Mattar, M, Rizvi, H, Woo, HJ, Shah, N, Nguyen, EM, Uddin, FZ, Quintanal-Villalonga, A, Chan, JM, Manoj, P, Allaj, V, Baine, MK, Bhanot, UK, Jain, M, Linkov, I, Meng, F, Brown, D, Chaft, JE, Plodkowski, AJ, Gigoux, M, Won, HH, Sen, T, Wells, DK, Donoghue, MTA, de Stanchina, E, Wolchok, JD, Loomis, B, Merghoub, T, Rudin, CM, Chow, A & Satpathy, AT 2023, 'Lineage tracing reveals clonal progenitors and long-term persistence of tumor-specific T cells during immune checkpoint blockade', Cancer Cell, vol. 41, no. 4, pp. 776-790.e7. https://doi.org/10.1016/j.ccell.2023.03.009

TY - JOUR

T1 - Lineage tracing reveals clonal progenitors and long-term persistence of tumor-specific T cells during immune checkpoint blockade

AU - Pai, Joy A.

AU - Hellmann, Matthew D.

AU - Sauter, Jennifer L.

AU - Mattar, Marissa

AU - Rizvi, Hira

AU - Woo, Hyung Jun

AU - Shah, Nisargbhai

AU - Nguyen, Evelyn M.

AU - Uddin, Fathema Z.

AU - Quintanal-Villalonga, Alvaro

AU - Chan, Joseph M.

AU - Manoj, Parvathy

AU - Allaj, Viola

AU - Baine, Marina K.

AU - Bhanot, Umesh K.

AU - Jain, Mala

AU - Linkov, Irina

AU - Meng, Fanli

AU - Brown, David

AU - Chaft, Jamie E.

AU - Plodkowski, Andrew J.

AU - Gigoux, Mathieu

AU - Won, Helen H.

AU - Sen, Triparna

AU - Wells, Daniel K.

AU - Donoghue, Mark T.A.

AU - de Stanchina, Elisa

AU - Wolchok, Jedd D.

AU - Loomis, Brian

AU - Merghoub, Taha

AU - Rudin, Charles M.

AU - Chow, Andrew

AU - Satpathy, Ansuman T.

PY - 2023/4/10

Y1 - 2023/4/10

N2 - 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.

AB - 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.

KW - TCF-1 progenitor exhausted T cells

KW - exhausted T cells

KW - immune checkpoint blockade

KW - lung cancer

KW - single-cell RNA/TCR sequencing

KW - tumor-specific T cells

UR - https://www.scopus.com/pages/publications/85151836836

U2 - 10.1016/j.ccell.2023.03.009

DO - 10.1016/j.ccell.2023.03.009

M3 - Article

C2 - 37001526

AN - SCOPUS:85151836836

SN - 1535-6108

VL - 41

SP - 776-790.e7

JO - Cancer Cell

JF - Cancer Cell

IS - 4

ER -

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

Abstract

Keywords

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