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ResearchIn-Press PreviewImmunologyNephrology Open Access | 10.1172/jci.insight.165108

Tertiary lymphoid structure signatures are associated with immune checkpoint inhibitor related acute interstitial nephritis

Shailbala Singh,1 James P. Long,2 Amanda Tchakarov,3 Yanlan Dong,4 Cassian Yee,1 and Jamie S. Lin4

1Department of Melanoma Medical Oncology, UT MD Anderson Cancer Center, Houston, United States of America

2Department of Biostatistics, UT MD Anderson Cancer Center, Houston, United States of America

3Department of Pathology and Laboratory Medicine, The University of Texas Health Science Center at McGovern Medical School, Houston, United States of America

4Section of Nephrology, UT MD Anderson Cancer Center, Houston, United States of America

Find articles by Singh, S. in: JCI | PubMed | Google Scholar |

1Department of Melanoma Medical Oncology, UT MD Anderson Cancer Center, Houston, United States of America

2Department of Biostatistics, UT MD Anderson Cancer Center, Houston, United States of America

3Department of Pathology and Laboratory Medicine, The University of Texas Health Science Center at McGovern Medical School, Houston, United States of America

4Section of Nephrology, UT MD Anderson Cancer Center, Houston, United States of America

Find articles by Long, J. in: JCI | PubMed | Google Scholar |

1Department of Melanoma Medical Oncology, UT MD Anderson Cancer Center, Houston, United States of America

2Department of Biostatistics, UT MD Anderson Cancer Center, Houston, United States of America

3Department of Pathology and Laboratory Medicine, The University of Texas Health Science Center at McGovern Medical School, Houston, United States of America

4Section of Nephrology, UT MD Anderson Cancer Center, Houston, United States of America

Find articles by Tchakarov, A. in: JCI | PubMed | Google Scholar |

1Department of Melanoma Medical Oncology, UT MD Anderson Cancer Center, Houston, United States of America

2Department of Biostatistics, UT MD Anderson Cancer Center, Houston, United States of America

3Department of Pathology and Laboratory Medicine, The University of Texas Health Science Center at McGovern Medical School, Houston, United States of America

4Section of Nephrology, UT MD Anderson Cancer Center, Houston, United States of America

Find articles by Dong, Y. in: JCI | PubMed | Google Scholar

1Department of Melanoma Medical Oncology, UT MD Anderson Cancer Center, Houston, United States of America

2Department of Biostatistics, UT MD Anderson Cancer Center, Houston, United States of America

3Department of Pathology and Laboratory Medicine, The University of Texas Health Science Center at McGovern Medical School, Houston, United States of America

4Section of Nephrology, UT MD Anderson Cancer Center, Houston, United States of America

Find articles by Yee, C. in: JCI | PubMed | Google Scholar |

1Department of Melanoma Medical Oncology, UT MD Anderson Cancer Center, Houston, United States of America

2Department of Biostatistics, UT MD Anderson Cancer Center, Houston, United States of America

3Department of Pathology and Laboratory Medicine, The University of Texas Health Science Center at McGovern Medical School, Houston, United States of America

4Section of Nephrology, UT MD Anderson Cancer Center, Houston, United States of America

Find articles by Lin, J. in: JCI | PubMed | Google Scholar |

Published December 6, 2022 - More info

JCI Insight. https://doi.org/10.1172/jci.insight.165108.
Copyright © 2022, Singh et al. This work is licensed under the Creative Commons Attribution 4.0 International License. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.
Published December 6, 2022 - Version history
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Abstract

Tertiary lymphoid structures (TLSs) are associated with anti-tumor response following immune checkpoint inhibitor (ICI) therapy, but a commensurate observation of TLS is absent for immune related adverse events (irAEs) i.e. acute interstitial nephritis (AIN). We hypothesized that TLS-associated inflammatory gene signatures are present in AIN and performed NanoString-based gene expression and multiplex 12-chemokine profiling on paired kidney tissue, urine and plasma specimens of 36 participants who developed acute kidney injury (AKI) on ICI therapy: AIN (18), acute tubular necrosis (9), or HTN nephrosclerosis (9). Increased T and B cell scores, a Th1-CD8+ T cell axis accompanied by interferon-g and TNF superfamily signatures were detected in the ICI-AIN group. TLS signatures were significantly increased in AIN cases and supported by histopathological identification. Furthermore, urinary TLS signature scores correlated with ICI-AIN diagnosis but not paired plasma. Urinary CXCL9 correlated best to tissue CXCL9 expression (rho 0.75, p < 0.001) and the ability to discriminate AIN vs. non-AIN (AUC 0.781, p-value 0.003). For the first time, we report the presence of TLS signatures in irAEs, define distinctive immune signatures, identify chemokine markers distinguishing ICI-AIN from common AKI etiologies and demonstrate that urine chemokine markers may be used as a surrogate for ICI-AIN diagnoses.

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