Progressive immune dysfunction with advancing disease stage in renal cell carcinoma

David A Braun; Kelly Street; Kelly P. Burke; David L. Cookmeyer; Thomas Denize; Christina B. Pedersen; Satyen H. Gohil; Nicholas Schindler; Lucas Pomerance; Laure Hirsch; Ziad Bakouny; Yue Hou; Juliet Forman; Teddy Huang; Shuqiang Li; Ang Cui; Derin B. Keskin; John Steinharter; Gabrielle Bouchard; Maxine Sun; Erica M. Pimenta; Wenxin Xu; Kathleen M. Mahoney; Bradley A. McGregor; Michelle S. Hirsch; Steven L. Chang; Kenneth J. Livak; David F. McDermott; Sachet A. Shukla; Lars R. Olsen; Sabina Signoretti; Arlene H. Sharpe; Rafael A. Irizarry; Toni K. Choueiri; Catherine J. Wu

doi:10.1016/j.ccell.2021.02.013

Progressive immune dysfunction with advancing disease stage in renal cell carcinoma

David A Braun
, Kelly Street
, Kelly P. Burke
, David L. Cookmeyer
, Thomas Denize
, Christina B. Pedersen
, Satyen H. Gohil
, Nicholas Schindler
, Lucas Pomerance
, Laure Hirsch
, Ziad Bakouny
, Yue Hou
, Juliet Forman
, Teddy Huang
, Shuqiang Li
, Ang Cui
, Derin B. Keskin
, John Steinharter
, Gabrielle Bouchard
, Maxine Sun

Erica M. Pimenta, Wenxin Xu, Kathleen M. Mahoney, Bradley A. McGregor, Michelle S. Hirsch, Steven L. Chang, Kenneth J. Livak, David F. McDermott, Sachet A. Shukla, Lars R. Olsen, Sabina Signoretti, Arlene H. Sharpe, Rafael A. Irizarry, Toni K. Choueiri, Catherine J. Wu^*

^*Corresponding author for this work

Dana-Farber Cancer Institute
McLean Hospital
University College Hospital London
Broad Institute of Harvard University and Massachusetts Institute of Technology
Massachusetts General Hospital/Harvard Medical School

Research output: Contribution to journal › Journal article › Research › peer-review

Abstract

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.

Original language	English
Journal	Cancer Cell
Volume	39
Issue number	5
Pages (from-to)	632-648
ISSN	1535-6108
DOIs	https://doi.org/10.1016/j.ccell.2021.02.013
Publication status	Published - 2021

Bibliographical note

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

SDG 3 Good Health and Well-being

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10.1016/j.ccell.2021.02.013

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Braun, D. A., Street, K., Burke, K. P., Cookmeyer, D. L., Denize, T., Pedersen, C. B., Gohil, S. H., Schindler, N., Pomerance, L., Hirsch, L., Bakouny, Z., Hou, Y., Forman, J., Huang, T., Li, S., Cui, A., Keskin, D. B., Steinharter, J., Bouchard, G., ... Wu, C. J. (2021). Progressive immune dysfunction with advancing disease stage in renal cell carcinoma. Cancer Cell, 39(5), 632-648. https://doi.org/10.1016/j.ccell.2021.02.013

@article{04f73ef8663949988916d0c74486dfc3,

title = "Progressive immune dysfunction with advancing disease stage in renal cell carcinoma",

abstract = "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.",

author = "Braun, \{David A\} and Kelly Street and Burke, \{Kelly P.\} and Cookmeyer, \{David L.\} and Thomas Denize and Pedersen, \{Christina B.\} and Gohil, \{Satyen H.\} and Nicholas Schindler and Lucas Pomerance and Laure Hirsch and Ziad Bakouny and Yue Hou and Juliet Forman and Teddy Huang and Shuqiang Li and Ang Cui and Keskin, \{Derin B.\} and John Steinharter and Gabrielle Bouchard and Maxine Sun and Pimenta, \{Erica M.\} and Wenxin Xu and Mahoney, \{Kathleen M.\} and McGregor, \{Bradley A.\} and Hirsch, \{Michelle S.\} and Chang, \{Steven L.\} and Livak, \{Kenneth J.\} and McDermott, \{David F.\} and Shukla, \{Sachet A.\} and Olsen, \{Lars R.\} and Sabina Signoretti and Sharpe, \{Arlene H.\} and Irizarry, \{Rafael A.\} and Choueiri, \{Toni K.\} and Wu, \{Catherine J.\}",

year = "2021",

doi = "10.1016/j.ccell.2021.02.013",

language = "English",

volume = "39",

pages = "632--648",

journal = "Cancer Cell",

issn = "1535-6108",

publisher = "Cell Press",

number = "5",

}

Braun, DA, Street, K, Burke, KP, Cookmeyer, DL, Denize, T, Pedersen, CB, Gohil, SH, Schindler, N, Pomerance, L, Hirsch, L, Bakouny, Z, Hou, Y, Forman, J, Huang, T, Li, S, Cui, A, Keskin, DB, Steinharter, J, Bouchard, G, Sun, M, Pimenta, EM, Xu, W, Mahoney, KM, McGregor, BA, Hirsch, MS, Chang, SL, Livak, KJ, McDermott, DF, Shukla, SA, Olsen, LR, Signoretti, S, Sharpe, AH, Irizarry, RA, Choueiri, TK & Wu, CJ 2021, 'Progressive immune dysfunction with advancing disease stage in renal cell carcinoma', Cancer Cell, vol. 39, no. 5, pp. 632-648. https://doi.org/10.1016/j.ccell.2021.02.013

TY - JOUR

T1 - Progressive immune dysfunction with advancing disease stage in renal cell carcinoma

AU - Braun, David A

AU - Street, Kelly

AU - Burke, Kelly P.

AU - Cookmeyer, David L.

AU - Denize, Thomas

AU - Pedersen, Christina B.

AU - Gohil, Satyen H.

AU - Schindler, Nicholas

AU - Pomerance, Lucas

AU - Hirsch, Laure

AU - Bakouny, Ziad

AU - Hou, Yue

AU - Forman, Juliet

AU - Huang, Teddy

AU - Li, Shuqiang

AU - Cui, Ang

AU - Keskin, Derin B.

AU - Steinharter, John

AU - Bouchard, Gabrielle

AU - Sun, Maxine

AU - Pimenta, Erica M.

AU - Xu, Wenxin

AU - Mahoney, Kathleen M.

AU - McGregor, Bradley A.

AU - Hirsch, Michelle S.

AU - Chang, Steven L.

AU - Livak, Kenneth J.

AU - McDermott, David F.

AU - Shukla, Sachet A.

AU - Olsen, Lars R.

AU - Signoretti, Sabina

AU - Sharpe, Arlene H.

AU - Irizarry, Rafael A.

AU - Choueiri, Toni K.

AU - Wu, Catherine J.

PY - 2021

Y1 - 2021

N2 - 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.

AB - 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.

U2 - 10.1016/j.ccell.2021.02.013

DO - 10.1016/j.ccell.2021.02.013

M3 - Journal article

C2 - 33711273

SN - 1535-6108

VL - 39

SP - 632

EP - 648

JO - Cancer Cell

JF - Cancer Cell

IS - 5

ER -

Progressive immune dysfunction with advancing disease stage in renal cell carcinoma

Abstract

Bibliographical note

UN SDGs

Access to Document

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