Investigating the determinants of immunotherapy response in the primary tumour of clear cell renal cell carcinoma (RCC)

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.