Abstract 491: Melanoma patients with multi-Siglec ligands as profiled by HYDRA technology are refractory to PD1 blockade

Abstract

Abstract PD1/PD-L1 and CTLA-4 checkpoint blockade have revolutionized cancer therapy and led to cures in metastatic melanoma, but most patients develop primary and acquired resistance to these therapies. Treating this refractory population requires the discovery of new immune escape mechanisms. Sialic acid–binding immunoglobulin-type lectins (Siglecs) are expressed on the majority of white blood cells of the immune system, play critical roles in immune cell signaling and serve as immune checkpoints to prevent unwanted immune responses. Sialic acid is a ligand for inhibitory Siglecs; hypersialyation is a hallmark of poor prognosis and is believed to help tumors escape from immune surveillance. However, the role of hypersialylation in resistance to immune checkpoint therapies remains unexplored. To study if hypersialylation drives immune escape in melanoma, we profiled the immunosuppressive sialoglycans using Siglec-based high-affinity sialoglycan-binding constructs called ‘HYDRAs'. The current study focuses on understanding Siglec-3, -7 and -9 sialoglycan ligand expression on tumors using the HYDRA-3, -7 and -9 platform, because these Siglecs are the major inhibitory Siglecs on both innate and adaptive immune cells among the fourteen Siglecs in humans. Serial sections from melanoma tumors and healthy tissues were stained with HYDRA-3, -7 or -9 and scored using the semi-qualitative H-score method by a blinded pathologist. HYDRA IHC on healthy and cancerous human tissues demonstrate unique binding patterns with melanomas having high signals for HYDRA-3, -7 and -9. A pre-treatment checkpoint inhibitor therapy cohort (n=53), which contained responders (n=30) and non-responders (n=23) to either aPD1 or aPD1 and aCTLA-4 combination therapy was further studied. Serial sections from each patient was stained with HYDRA-3, -7 or -9 and scored using the semi-qualitative H-score method by our blinded pathologist. Cutoffs were determined in an unbiased manner for each HYDRA individually and each possible HYDRA combination to obtain correlations with patient progression-free and overall survival. A significant tumor H-score cutoff of a combined HYDRA-3 and -7 correlated with poor outcomes. This HYDRA-3 and -7 cutoff did not correlate with other melanoma biomarkers such as BRAF-mutation, liver metastases, PD-L1, nor TILs, suggesting a unique biology independent of these markers. We discovered that melanoma patients with multi-Siglec ligands as profiled by HYDRAs tend to be resistant to PD-1 checkpoint blockade and can be candidates for novel treatments targeting the Siglec-Sialoglycan axis. A larger cohort and longitudinal study are currently underway to examine the Siglec-Sialoglycan axis of immunosuppression in melanoma and late-breaking results will be included in this poster. Citation Format: Adam Petrone, Dennie T. Frederick, Jillian M. Prendergast, James Broderick, Karl Normington, Genevieve Boland, Li Peng. Melanoma patients with multi-Siglec ligands as profiled by HYDRA technology are refractory to PD1 blockade [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 491.