Cystatin C is glucocorticoid responsive, directs recruitment of Trem2+ macrophages, and predicts failure of cancer immunotherapy

Sam O. Kleeman; Tuba Mansoor Thakir; Breanna Demestichas; Nicholas Mourikis; Dominik Loiero; Miriam Ferrer; Sean Bankier; Yosef J.R.A. Riazat-Kesh; Hassal Lee; Dimitrios Chantzichristos; Claire Regan; Jonathan Preall; Sarthak Sinha; Nicole Rosin; Bryan Yipp; Luiz G.N. de Almeida; Jeff Biernaskie; Antoine Dufour; Pinkus Tober-Lau; Arno Ruusalepp; Johan L.M. Bjorkegren; Markus Ralser; Florian Kurth; Vadim Demichev; Todd Heywood; Qing Gao; Gudmundur Johannsson; Viktor H. Koelzer; Brian R. Walker; Hannah V. Meyer; Tobias Janowitz

doi:10.1016/j.xgen.2023.100347

Cystatin C is glucocorticoid responsive, directs recruitment of Trem2+ macrophages, and predicts failure of cancer immunotherapy

Sam O. Kleeman
, Tuba Mansoor Thakir
, Breanna Demestichas
, Nicholas Mourikis
, Dominik Loiero
, Miriam Ferrer
, Sean Bankier
, Yosef J.R.A. Riazat-Kesh
, Hassal Lee
, Dimitrios Chantzichristos
, Claire Regan
, Jonathan Preall
, Sarthak Sinha
, Nicole Rosin
, Bryan Yipp
, Luiz G.N. de Almeida
, Jeff Biernaskie
, Antoine Dufour
, Pinkus Tober-Lau
, Arno Ruusalepp

Johan L.M. Bjorkegren, Markus Ralser, Florian Kurth, Vadim Demichev, Todd Heywood, Qing Gao, Gudmundur Johannsson, Viktor H. Koelzer, Brian R. Walker, Hannah V. Meyer, Tobias Janowitz

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

29 Scopus citations

Abstract

Cystatin C (CyC), a secreted cysteine protease inhibitor, has unclear biological functions. Many patients exhibit elevated plasma CyC levels, particularly during glucocorticoid (GC) treatment. This study links GCs with CyC's systemic regulation by utilizing genome-wide association and structural equation modeling to determine CyC production genetics in the UK Biobank. Both CyC production and a polygenic score (PGS) capturing predisposition to CyC production were associated with increased all-cause and cancer-specific mortality. We found that the GC receptor directly targets CyC, leading to GC-responsive CyC secretion in macrophages and cancer cells. CyC-knockout tumors displayed significantly reduced growth and diminished recruitment of TREM2+ macrophages, which have been connected to cancer immunotherapy failure. Furthermore, the CyC-production PGS predicted checkpoint immunotherapy failure in 685 patients with metastatic cancer from combined clinical trial cohorts. In conclusion, CyC may act as a GC effector pathway via TREM2+ macrophage recruitment and may be a potential target for combination cancer immunotherapy.

Original language	English
Article number	100347
Journal	Cell Genomics
Volume	3
Issue number	8
DOIs	https://doi.org/10.1016/j.xgen.2023.100347
State	Published - 9 Aug 2023

Keywords

GWAS
PGS
cystatin C
glucocorticoids
immunotherapy
macrophages
renal function

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10.1016/j.xgen.2023.100347

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Kleeman, S. O., Thakir, T. M., Demestichas, B., Mourikis, N., Loiero, D., Ferrer, M., Bankier, S., Riazat-Kesh, Y. J. R. A., Lee, H., Chantzichristos, D., Regan, C., Preall, J., Sinha, S., Rosin, N., Yipp, B., de Almeida, L. G. N., Biernaskie, J., Dufour, A., Tober-Lau, P., ... Janowitz, T. (2023). Cystatin C is glucocorticoid responsive, directs recruitment of Trem2+ macrophages, and predicts failure of cancer immunotherapy. Cell Genomics, 3(8), Article 100347. https://doi.org/10.1016/j.xgen.2023.100347

@article{13506c0045d74daaa4a3804b6a29ebe8,

title = "Cystatin C is glucocorticoid responsive, directs recruitment of Trem2+ macrophages, and predicts failure of cancer immunotherapy",

abstract = "Cystatin C (CyC), a secreted cysteine protease inhibitor, has unclear biological functions. Many patients exhibit elevated plasma CyC levels, particularly during glucocorticoid (GC) treatment. This study links GCs with CyC's systemic regulation by utilizing genome-wide association and structural equation modeling to determine CyC production genetics in the UK Biobank. Both CyC production and a polygenic score (PGS) capturing predisposition to CyC production were associated with increased all-cause and cancer-specific mortality. We found that the GC receptor directly targets CyC, leading to GC-responsive CyC secretion in macrophages and cancer cells. CyC-knockout tumors displayed significantly reduced growth and diminished recruitment of TREM2+ macrophages, which have been connected to cancer immunotherapy failure. Furthermore, the CyC-production PGS predicted checkpoint immunotherapy failure in 685 patients with metastatic cancer from combined clinical trial cohorts. In conclusion, CyC may act as a GC effector pathway via TREM2+ macrophage recruitment and may be a potential target for combination cancer immunotherapy.",

keywords = "GWAS, PGS, cystatin C, glucocorticoids, immunotherapy, macrophages, renal function",

author = "Kleeman, \{Sam O.\} and Thakir, \{Tuba Mansoor\} and Breanna Demestichas and Nicholas Mourikis and Dominik Loiero and Miriam Ferrer and Sean Bankier and Riazat-Kesh, \{Yosef J.R.A.\} and Hassal Lee and Dimitrios Chantzichristos and Claire Regan and Jonathan Preall and Sarthak Sinha and Nicole Rosin and Bryan Yipp and \{de Almeida\}, \{Luiz G.N.\} and Jeff Biernaskie and Antoine Dufour and Pinkus Tober-Lau and Arno Ruusalepp and Bjorkegren, \{Johan L.M.\} and Markus Ralser and Florian Kurth and Vadim Demichev and Todd Heywood and Qing Gao and Gudmundur Johannsson and Koelzer, \{Viktor H.\} and Walker, \{Brian R.\} and Meyer, \{Hannah V.\} and Tobias Janowitz",

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

year = "2023",

month = aug,

day = "9",

doi = "10.1016/j.xgen.2023.100347",

language = "English",

volume = "3",

journal = "Cell Genomics",

issn = "2666-979X",

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Kleeman, SO, Thakir, TM, Demestichas, B, Mourikis, N, Loiero, D, Ferrer, M, Bankier, S, Riazat-Kesh, YJRA, Lee, H, Chantzichristos, D, Regan, C, Preall, J, Sinha, S, Rosin, N, Yipp, B, de Almeida, LGN, Biernaskie, J, Dufour, A, Tober-Lau, P, Ruusalepp, A, Bjorkegren, JLM, Ralser, M, Kurth, F, Demichev, V, Heywood, T, Gao, Q, Johannsson, G, Koelzer, VH, Walker, BR, Meyer, HV & Janowitz, T 2023, 'Cystatin C is glucocorticoid responsive, directs recruitment of Trem2+ macrophages, and predicts failure of cancer immunotherapy', Cell Genomics, vol. 3, no. 8, 100347. https://doi.org/10.1016/j.xgen.2023.100347

TY - JOUR

T1 - Cystatin C is glucocorticoid responsive, directs recruitment of Trem2+ macrophages, and predicts failure of cancer immunotherapy

AU - Kleeman, Sam O.

AU - Thakir, Tuba Mansoor

AU - Demestichas, Breanna

AU - Mourikis, Nicholas

AU - Loiero, Dominik

AU - Ferrer, Miriam

AU - Bankier, Sean

AU - Riazat-Kesh, Yosef J.R.A.

AU - Lee, Hassal

AU - Chantzichristos, Dimitrios

AU - Regan, Claire

AU - Preall, Jonathan

AU - Sinha, Sarthak

AU - Rosin, Nicole

AU - Yipp, Bryan

AU - de Almeida, Luiz G.N.

AU - Biernaskie, Jeff

AU - Dufour, Antoine

AU - Tober-Lau, Pinkus

AU - Ruusalepp, Arno

AU - Bjorkegren, Johan L.M.

AU - Ralser, Markus

AU - Kurth, Florian

AU - Demichev, Vadim

AU - Heywood, Todd

AU - Gao, Qing

AU - Johannsson, Gudmundur

AU - Koelzer, Viktor H.

AU - Walker, Brian R.

AU - Meyer, Hannah V.

AU - Janowitz, Tobias

PY - 2023/8/9

Y1 - 2023/8/9

N2 - Cystatin C (CyC), a secreted cysteine protease inhibitor, has unclear biological functions. Many patients exhibit elevated plasma CyC levels, particularly during glucocorticoid (GC) treatment. This study links GCs with CyC's systemic regulation by utilizing genome-wide association and structural equation modeling to determine CyC production genetics in the UK Biobank. Both CyC production and a polygenic score (PGS) capturing predisposition to CyC production were associated with increased all-cause and cancer-specific mortality. We found that the GC receptor directly targets CyC, leading to GC-responsive CyC secretion in macrophages and cancer cells. CyC-knockout tumors displayed significantly reduced growth and diminished recruitment of TREM2+ macrophages, which have been connected to cancer immunotherapy failure. Furthermore, the CyC-production PGS predicted checkpoint immunotherapy failure in 685 patients with metastatic cancer from combined clinical trial cohorts. In conclusion, CyC may act as a GC effector pathway via TREM2+ macrophage recruitment and may be a potential target for combination cancer immunotherapy.

AB - Cystatin C (CyC), a secreted cysteine protease inhibitor, has unclear biological functions. Many patients exhibit elevated plasma CyC levels, particularly during glucocorticoid (GC) treatment. This study links GCs with CyC's systemic regulation by utilizing genome-wide association and structural equation modeling to determine CyC production genetics in the UK Biobank. Both CyC production and a polygenic score (PGS) capturing predisposition to CyC production were associated with increased all-cause and cancer-specific mortality. We found that the GC receptor directly targets CyC, leading to GC-responsive CyC secretion in macrophages and cancer cells. CyC-knockout tumors displayed significantly reduced growth and diminished recruitment of TREM2+ macrophages, which have been connected to cancer immunotherapy failure. Furthermore, the CyC-production PGS predicted checkpoint immunotherapy failure in 685 patients with metastatic cancer from combined clinical trial cohorts. In conclusion, CyC may act as a GC effector pathway via TREM2+ macrophage recruitment and may be a potential target for combination cancer immunotherapy.

KW - GWAS

KW - PGS

KW - cystatin C

KW - glucocorticoids

KW - immunotherapy

KW - macrophages

KW - renal function

UR - https://www.scopus.com/pages/publications/85169808030

U2 - 10.1016/j.xgen.2023.100347

DO - 10.1016/j.xgen.2023.100347

M3 - Article

AN - SCOPUS:85169808030

SN - 2666-979X

VL - 3

JO - Cell Genomics

JF - Cell Genomics

IS - 8

M1 - 100347

ER -

Cystatin C is glucocorticoid responsive, directs recruitment of Trem2+ macrophages, and predicts failure of cancer immunotherapy

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Keywords

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