Association of myeloid-derived suppressor cell (MDSC) dynamics with clinical response to nivolumab in metastatic clear cell renal carcinoma patients (mRCC): Results from the I-RENE Meet-URO 8 study.

586 Background: Immune checkpoint blockade is a standard-of-care treatment for mRCC patients, but the immune mechanisms driving clinical benefit remain underexplored. In the I-RENE trial (NCT04891055), we conducted a comprehensive evaluation of myeloid-derived suppressor cell (MDSC) and lymphoid dynamics and their impact on the efficacy of nivolumab. Methods: The I-RENE study is a prospective, translational, real-world multicenter trial involving mRCC patients treated with nivolumab after failure of previous VEGFR-targeted therapies. Sixty patients were enrolled between December 2018 and August 2022. Peripheral blood (PB) samples were collected at baseline and at 2, 4, and 12 weeks, as well as at disease progression. PBMCs were analyzed by high-resolution flow cytometry (profiling 144 lymphoid and myeloid cell subsets), and plasma was assessed using multiplex analysis (69 soluble factors). CD14+ monocytes from PB and tumor tissue were subjected to RNA sequencing. Results: Significant immune modulations in PB were detectable as early as 2 weeks into treatment across all patients, regardless of clinical response, and persisted throughout the 3-month observation period. These changes included substantial alterations in the profiles of immune cells and plasma soluble factors. Responders to nivolumab exhibited a marked reduction in monocyte subsets associated with immune suppression, such as CD14+HLA-DR- cells, CD14+PD-L1+ cells, and intermediate monocytes. In contrast, non-responders showed a progressive increase in suppressive monocytes and a concomitant decrease in CD14+ cells involved in anti-tumor immunity, including non-classical monocytes and CD14+ cells expressing HLA-DR and CX3CR1. Lymphoid compartment analysis revealed that responders experienced an increase in CD8+ T cells and CD4+ effector memory T cells, along with a reduction in CD38+ T cells. Conversely, non-responders showed significant upregulation of senescent CD8+ T cells (KLRG1+CD28-CD57+) and CD38+ T cells. All progressing patients showed a notable resurgence of suppressive myeloid cells (HLA-DR-, PD-L1+), confirmed by an enriched MDSC gene signature, as well as an increase in PB CD38+ and senescent T cells. Notably, the detrimental role of myeloid-driven immune suppression in non-responders was further confirmed by an enriched MDSC gene signature in matched tumor samples. Conclusions: The pervasive and detrimental impact of myeloid cells committed to immune suppression is evident even before radiological progression in mRCC patients and persists despite immunotherapy. These findings highlight the need for early identification of immune-suppressive infiltrates and the development of strategies to overcome or reprogram these cells, both at the systemic and tumor level, following diagnosis.