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.