268O - Determinants of neoadjuvant immune checkpoint inhibitor plus tyrosine kinase inhibitor therapy response in renal cell carcinoma

Background

Radical nephrectomy with thrombectomy was associated with high surgical morbidity and mortality. Preoperative tumor thrombus downgrading may reduce surgical coverage and surgical complications. However, the response to neoadjuvant immune and targeted combination therapy (NCT) varies in renal cell carcinoma with venous tumor thrombus (RCC-TT).

Methods

Based on the multicenter clinical trial, we prospectively collected nine biopsy samples prior to NCT and thirteen surgical samples after NCT for RCC-TT. These samples were then subjected to scRNA-seq analysis. Leveraging bioinformatics tools like unsupervised clustering, pseudo-time sequence analysis, and cell interaction analysis, a comprehensive dataset encompassing 184,972 cells was assembled for in-depth examination.

Results

We divided the tumor cells into 11 distinct subsets, uncovering a subpopulation that exhibited specific overexpression of Serum Amyloid A (SAA). Our analysis revealed that patients with high SAA expression exhibited a worse response to NCT and had a poorer prognosis. Notably, SAA+ tumors displayed a unique differentiation trajectory, which can transform to Tumor_03_SERPINE1 and Tumor_07_CCL2. In addition, we further classified neutrophils into seven subsets and observed a characteristic differentiation pattern from Neu_5_MMP9 to the Neu_06_LDHA. Mechanistic investigations suggested that SAA secreted by SAA-positive tumor cells may act on neutrophils, prompting the differentiation of MMP9+ neutrophils into LDHA+ neutrophils, leading to metabolic reprogramming of neutrophils. Consequently, SAA+ tumors have complex interactions with neutrophils and T cells, potentially cultivating an immunosuppressive tumor microenvironment.

Conclusions

This study underscores the potential of SAA as a crucial biomarker in predicting NCT resistance in RCC-TT. Targeting tumor cells with high SAA expression or SAA-induced immunosuppressive tumor microenvironment may offer a promising strategy to overcome NCT resistance, thereby enhancing treatment outcomes in these patients. Consequently, high SAA expression in tumor cells may play a pivotal role in mediating drug resistance to NCT in RCC-TT.

Clinical trial identification

Editorial acknowledgement

Legal entity responsible for the study

The authors.

Funding

Has not received any funding.

Disclosure

All authors have declared no conflicts of interest.