Introduction: Since CARMENA trial found non-inferiority of sunitinib alone, the contemporary role of cytoreductive nephrectomy (CN) has been significantly downsized. However, updated CARMENA trial results demonstrated certain subsets with metastatic renal cell carcinoma (mRCC) may still benefit from CN. We tried to assess the role of CN in combination with immune checkpoint inhibitor (ICI) from the perspective tumor immune microenvironment (TIME). Methods: Low- and high-tumor burden pulmonary metastatic orthotopic murine mRCC models have been developed. Anti-PD-1 and anti-CTLA-4 antibodies were systemically injected through the peritoneum every 3 days. Renca implanted kidney was removed in the CN performed group. For the upfront CN plus ICI group, CN was performed 1 day before the ICI, while CN was performed 5 days after ICI for the deferred CN plus ICI group. The remodeling of the TIME was determined using immunofluorescence analysis. Results: Low- and high-tumor burden murine mRCC models have been successfully developed with statistically significant difference in median survival (P <0.05). In low-tumor burden model (Figure 1A), upfront CN plus ICI group demonstrated significantly better survival outcomes compared to deferred CN plus ICI group. In high-tumor burden model (Figure 1B), similar results were shown as low-tumor burden model, except no significant survival difference between ICI only and CN only group, and between upfront CN plus ICI and deferred CN plus ICI group. Immunofluorescence analysis demonstrated that CN modulate TIME by increasing M1 tumor-associated macrophage (TAM) and at the same time decreasing M2 TAM (Figure 2). Conclusions: This study is the first animal study to demonstrate the role of CN in combination with ICI. We have shown that the CN has certain role in the immune-oncology (IO) era and was associated with improved survival by the regulation of M1 and M2 TAM. CN also regulated myeloid-derived suppressor cells and regulatory T cells in combination with ICIs although not to be significant in our study. SOURCE OF Funding: This work was supported by a grant from the Korea Health Technology R&D Project through the Korea Health Industry Development Institute funded by the Ministry of Health & Welfare, Republic of Korea [grant number: HI17C1095], and the National Research Foundation of Korea (NRF) grant funded by the Korean government (MSIT) [grant number: 2019R1A2C1002863 and 2022R1A2C2003831].
