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Published on: January 22, 2013
Comprehensive tumor-immune profiling reveals mediators of paradoxical immune sensitivity in sarcomatoid renal cell
Nicholas J Salgia1, Adil Khan2, Wilhelm M Aubrecht2
1Department of Immunology, Roswell Park Comprehensive Cancer Center, Buffalo, NY 14263, USA; MD-PhD Program, University at Buffalo Jacobs School of Medicine and Biomedical Sciences, Buffalo, NY 14263, USA.
Abstract:
Renal cell carcinoma with sarcomatoid features (sRCC) is a highly aggressive tumor type yet preferentially responds to immune checkpoint blockade (ICB). To better understand microenvironmental mediators of this paradoxical immune sensitivity, we performed single-cell analyses of human sRCC tumors compared against clear cell RCC (ccRCC), with validation spatially and in bulk transcriptomic datasets totaling over 3,000 RCC tumors. We describe a robust immune network in sRCC using these orthogonal approaches: tumor-infiltrating T cells in sRCC are more activated, and subsequently exhausted, while being enriched for CXCL13 expression. Congruently, tertiary lymphoid structures are pervasive in sRCC, paralleling functional enrichment of humoral immune activity. Tumor clone analysis revealed increased iron-associated programs in sRCC, presenting a potential vulnerability. We furthermore leveraged the paradoxical biology of sRCC to derive a genomic dedifferentiation signature (GDS) that, while negatively prognostic, identifies patients most likely to benefit from ICB across cohorts and tumor types.
Insights
Sarcomatoid renal cell carcinoma (sRCC) shows paradoxical immune sensitivity. Researchers identified unique immune networks and iron-associated programs in sRCC, revealing potential therapeutic vulnerabilities and a signature predicting response to immune checkpoint blockade (ICB).
Area of Science:
- Oncology
- Immunology
- Genomics
Background:
- Sarcomatoid renal cell carcinoma (sRCC) is aggressive but uniquely responsive to immune checkpoint blockade (ICB).
- Understanding the tumor microenvironment of sRCC is crucial for explaining its immune sensitivity.
Purpose of the Study:
- To investigate the immune microenvironment of sRCC compared to clear cell RCC (ccRCC).
- To identify mediators of ICB sensitivity in sRCC.
- To discover potential therapeutic vulnerabilities and predictive biomarkers for ICB.
Main Methods:
- Single-cell RNA sequencing of human sRCC and ccRCC tumors.
- Spatial and bulk transcriptomic analyses of over 3,000 RCC tumors.
- Tumor clone analysis and genomic profiling.
Main Results:
- sRCC exhibits a distinct immune network with activated and exhausted T cells expressing CXCL13.
- Tertiary lymphoid structures and humoral immune activity are prevalent in sRCC.
- Increased iron-associated programs were identified in sRCC, suggesting a potential vulnerability.
Conclusions:
- sRCC possesses a unique immune microenvironment contributing to its sensitivity to ICB.
- A derived genomic dedifferentiation signature (GDS) predicts ICB benefit across tumor types.
- Targeting iron-associated programs may represent a novel therapeutic strategy for sRCC.
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