LB1657 Tie-2 expressing monocytic myeloid-derived suppressor cells represent a resistance mechanism to anti-PD-1 therapy in melanoma

Recently, the rate of TIE-2 expressing monocytic myeloid-derived suppressor cells (TIE-2+ M-MDSC) was described as a negative prognostic marker for melanoma patients. TIE-2 is expressed mainly in the membrane of endothelial cells, and it is the receptor of the pro-angiogenic factor angiopoietin-2 (ANGPT2). In this study, we investigated the impact of TIE-2+ M-MDSC on response to anti-PD-1 therapy in advanced melanoma patients. Patients with melanoma treated with anti-PD-1 therapy (n=56) from immunomonitoring cohorts (LYTELOMEL study, NCT02838433) were studied. Blood samples were collected at baseline before immunotherapy. The rate of TIE-2+ M-MDSC was analyzed in PBMC by flow cytometry and angiopoietin-2 was dosed by ELISA in serum. Transcriptomic analysis was performed with RNA sequencing in TIE-2+ M-MDSC. Objectif response rate (ORR) was defined according to recist criteria. Two groups of patients were discriminated according to the level of TIE-2 on M-MDSC (threshold at 5,6%): patients with TIE-2High M-MDSC (n=26) and with TIE-2Low M-MDSC (n=27). ORR was 97% (25/27) in the TIE-2Low M-MDSC group compared to 50% (13/26) in the TIE-2High M-MDSC group (p=0,0023). A similar trend was observed in the ANGPT2High group compared to the ANGPT2 Low group (89% vs 60% p=0,079). In contrast, ORR was 39% (n=7/18) in patients exhibiting high blood levels of TIE-2 M-MDSC and ANGPT2. Transcriptomic analysis of TIE-2 M-MDSC isolated in the context of TIE-2/ANGPT2High signature found that these cells overexpressed pathways associated with MDSC differentiation, angiogenesis, and immune suppression. Thus, these results suggest that TIE-2high M-MDSC/ANG2highaxis is involved in primary resistance to anti-PD-1 in melanoma.