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Updated: Jul 7, 2026
The Use of Reverse Phase Protein Arrays (RPPA) to Explore Protein Expression Variation within Individual Renal Cell Cancers
Published on: January 22, 2013
Investigating the determinants of immunotherapy response in the primary tumour of clear cell renal cell carcinoma
Cerise Tang1, Deepak Poduval1, Suzanna Lee2
1Yale Center of Cellular and Molecular Oncology, Yale School of Medicine, New Haven, Connecticut, USA.
Objective:
Immune checkpoint inhibitors (ICIs) have demonstrated durable clinical benefit in a subset of patients with metastatic renal cell carcinoma (RCC), yet the molecular features that govern therapeutic response within the primary tumour remain poorly defined. This is of particular importance in the current era, where cytoreductive nephrectomy is less commonly performed and many patients with metastatic disease still have the primary RCC tumour in place. To deepen our understanding of ICI response in the primary tumour and to understand the evolution of RCC on ICI, we conducted a comprehensive genomic analysis of paired pretreatment and post-treatment primary RCC tumours treated with ICI.
Design Setting And Participants:
We performed a multimodal analysis of 46 ICI-treated primary RCC tumour specimens from 33 patients, including 13 matched pretreatment biopsies and post-treatment nephrectomies to investigate the genomic and transcriptomic evolution of tumours exposed to ICI therapy. Seventeen samples were from responders (>30% radiographic shrinkage, n=4 pretreatment, n=13 post-treatment) and 29 samples were from non-responders (<30% shrinkage, n=11 pretreatment, n=18 post-treatment). Whole-exome and RNA-seq were performed at Caris Life Sciences.
Results:
In this limited cohort, pretreatment responder biopsies are enriched for immune-related gene programmes, including B cell and tertiary lymphoid structure signatures. Longitudinal analysis reveals immune pathways decline in responders while non-responders show signatures of T cell exhaustion. However, the small number of patients with paired samples constrains statistical power and limits generalisability.
Conclusions:
Our findings highlight the value of primary tumour profiling in understanding ICI response dynamics in RCC.
Insights
Molecular features in primary renal cell carcinoma (RCC) tumors before and after immune checkpoint inhibitor (ICI) treatment were analyzed. Pretreatment responders showed immune gene signatures, while non-responders exhibited T cell exhaustion markers.
Area of Science:
- Oncology
- Immunology
- Genomics
Background:
- Immune checkpoint inhibitors (ICIs) offer durable benefit for metastatic renal cell carcinoma (RCC) patients, but primary tumor molecular features predicting response are unclear.
- Cytoreductive nephrectomy is less common, making primary tumor analysis crucial for understanding ICI response and RCC evolution during therapy.
Purpose of the Study:
- To comprehensively analyze genomic and transcriptomic changes in paired pretreatment and post-treatment primary RCC tumors from patients treated with ICIs.
- To identify molecular features associated with ICI response and tumor evolution in RCC.
Main Methods:
- Multimodal analysis of 46 primary RCC tumor specimens (13 matched pairs) from 33 patients treated with ICIs.
- Whole-exome and RNA sequencing performed on pretreatment biopsies and post-treatment nephrectomies.
- Tumor samples categorized into responders and non-responders based on radiographic shrinkage.
Main Results:
- Pretreatment biopsies from responders were enriched for immune-related gene programs, including B cell and tertiary lymphoid structure signatures.
- Longitudinal analysis indicated a decline in immune pathways in responders and signatures of T cell exhaustion in non-responders.
- The limited number of paired samples restricts statistical power and generalizability.
Conclusions:
- Primary tumor profiling is valuable for understanding ICI response dynamics in RCC.
- Identifying specific immune signatures in pretreatment tumors may help predict ICI efficacy.
