Cross-species analysis reveals clonotypic T-cell remodeling underlying adrenal resistance to PD-1 blockade
Abstract
Although clinical data suggest that adrenal metastases from solid tumors are less responsive to immune checkpoint inhibition (ICI) compared to other organ sites, little is known about the adrenal immune microenvironment’s role in metastatic growth and response to immunotherapy. Using a novel clinical and genomic database of renal cell carcinoma (RCC) patients, matched human adrenal and PBMC specimens, and orthotopic murine tumors, we identified an adrenal immune state enriched for PD-1+ activated, effector memory, and tissue-resident T cells rather than an immune desert. Paired single-cell RNA (scRNA) and T cell receptor (TCR) sequencing of benign adrenal tissue and peripheral blood showed reproducible adrenal enrichment of activation, hypoxia, TNF-NF-κB, and mTORC1 programs, reduced repertoire diversity, and tissue-dependent state remodeling between shared clonotypes. In Renca and MC-38 tumor models, adrenal tumors showed attenuated and less durable responses to PD-1 blockade compared to subcutaneous tumors, and Renca adrenal tumors failed to mount the treatment-associated effector memory response observed subcutaneously. Overall, our cross-species analysis identifies the adrenal gland as a distinct immune compartment with a unique population of adrenal PD-1+ T cells with resistance to ICI treatment despite an activated, effector phenotype.
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BibTeX
@misc{liu2026crossspecies,
title = {{Cross-species analysis reveals clonotypic T-cell remodeling underlying adrenal resistance to PD-1 blockade}},
author = {Natalie Liu and Jay Uppuluri and Clemens Van Dongen and Annie Trinh and Jessica Schmeling and Omolola Olaleye and Cyrus Sholevar and Thant Zaw and Makan Karimzadeh and Marshall Lammers and Megan Purl and Amjad Mansour and Trung Tran and Joanne Xiu and W. Kimryn Rathmell and William Becker and Jinhwan Kim and Shuchi Gulati and Karleen Meiklejohn and Michael Corwin and Arta Monjazeb and Claire Graves and William Murphy and Sean Judge and Michael Campbell and Anthony Zamora and Robert Canter},
howpublished = {Research Square},
year = {2026},
month = oct,
doi = {10.21203/rs.3.rs-11176760/v1},
url = {https://doi.org/10.21203/rs.3.rs-11176760/v1},
note = {CC BY 4.0},
}
RIS
TY - UNPB
TI - Cross-species analysis reveals clonotypic T-cell remodeling underlying adrenal resistance to PD-1 blockade
AU - Natalie Liu
AU - Jay Uppuluri
AU - Clemens Van Dongen
AU - Annie Trinh
AU - Jessica Schmeling
AU - Omolola Olaleye
AU - Cyrus Sholevar
AU - Thant Zaw
AU - Makan Karimzadeh
AU - Marshall Lammers
AU - Megan Purl
AU - Amjad Mansour
AU - Trung Tran
AU - Joanne Xiu
AU - W. Kimryn Rathmell
AU - William Becker
AU - Jinhwan Kim
AU - Shuchi Gulati
AU - Karleen Meiklejohn
AU - Michael Corwin
AU - Arta Monjazeb
AU - Claire Graves
AU - William Murphy
AU - Sean Judge
AU - Michael Campbell
AU - Anthony Zamora
AU - Robert Canter
PY - 2026
DA - 2026/10/16
PB - Research Square
DO - 10.21203/rs.3.rs-11176760/v1
UR - https://doi.org/10.21203/rs.3.rs-11176760/v1
AB - Although clinical data suggest that adrenal metastases from solid tumors are less responsive to immune checkpoint inhibition (ICI) compared to other organ sites, little is known about the adrenal immune microenvironment’s role in metastatic growth and response to immunotherapy. Using a novel clinical and genomic database of renal cell carcinoma (RCC) patients, matched human adrenal and PBMC specimens, and orthotopic murine tumors, we identified an adrenal immune state enriched for PD-1+ activated, effector memory, and tissue-resident T cells rather than an immune desert. Paired single-cell RNA (scRNA) and T cell receptor (TCR) sequencing of benign adrenal tissue and peripheral blood showed reproducible adrenal enrichment of activation, hypoxia, TNF-NF-κB, and mTORC1 programs, reduced repertoire diversity, and tissue-dependent state remodeling between shared clonotypes. In Renca and MC-38 tumor models, adrenal tumors showed attenuated and less durable responses to PD-1 blockade compared to subcutaneous tumors, and Renca adrenal tumors failed to mount the treatment-associated effector memory response observed subcutaneously. Overall, our cross-species analysis identifies the adrenal gland as a distinct immune compartment with a unique population of adrenal PD-1+ T cells with resistance to ICI treatment despite an activated, effector phenotype.
SN - 2693-5015
ER -