Background: In a single arm, open label phase 1b clinical trial the safety of neoadjuvant durvalumab +/- tremelimumab was studied in pts with (w) locally advanced RCC. Expression of IC molecules on immunomodulatory cells in peripheral blood (PB) and tumor (T) and the association w treatment (tx) was investigated. Methods: Pts with ≥ T2bN0-1M0 RCC received either durvalumab or combination durvalumab + tremelimumab prior to surgery. Blood samples were drawn prior to neoadjuvant tx, prior to surgery, and approximately 30 days after surgery before adjuvant tx. The percentage of MDSC (CD33+/HLADR-) and subtypes in PB and T and expression of PD1, PD-L1, and V-domain Ig suppressor of T cell activation (VISTA) were measured. MDSC subtypes included polymorphonuclear (PMN; CD15+/CD14-), monocytic (M; CD15-/CD14+) and uncommitted (UC; CD15-/CD14-). Linear mixed model was used for each MDSC subtype to estimate and compare cohorts over time. Results: Eighteen pts were enrolled: 4 women and 14 men, median age 62, 17 pts had T3-4 and 4 pts had N1 disease. Six pts received 1 dose of durvalumab and 12 pts received 1 dose of durvalumab + tremelimumab before surgery. Tx-related grade 3 adverse events (per CTCAE, v5.0) included thrombocytopenia, bilateral lower extremity weakness, hyperglycemia, chest pain, and diabetic ketoacidosis.One pt had grade 4 elevated lipase. One pt had sudden death from a non-drug related cardiac event 9 days after receiving combination therapy prior to surgery. PB and T samples from 17 pts were available. Expression of VISTA on M-MDSC and UC-MDSC were positively correlated in PB and T (Spearman’s rho = 0.61; P=0.03 for both). VISTA expression on UC-MDSC in PB was significantly higher in pts who received durvalumab monotherapy compared to those treated w durvalumab + tremelimumab (P=0.04). Frequencies of PD-L1 expression on M-MDSC and UC-MDSC in PB decreased significantly from pre- to post-neoadjuvant tx (P < 0.01). Conclusions: Neoadjuvant durvalumab + tremelimumab in pts w locally advanced RCC is feasible and affects the expression of IC molecules (PD-L1 and VISTA) on M-MDSC and UC-MDSC. Clinical trial information: NCT02762006