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Background Immune checkpoint inhibitor (ICI) therapy has revolutionized the treatment of lung cancer, though only a subset of patients experience response. To this end, further molecular characterization of responders and non-responders is necessary. The CyTOF platform has the capability of discerning populations of immune cells expressing cancer-related proteins, and similarly, circulating glycoproteins have their glycans modulated during an immune response or in the presence of a tumor. This combination of immune biomarkers has not been jointly assessed in the ICI context.Methods The CyTOF and GlycoVision platforms were employed to assess n=98 cell population protein markers and n=607 glycopeptide biomarkers in advanced lung cancer patients (n=29 non-small cell and n=2 small cell, respectively) treated with Pembrolizumab, Nivolumab or Durvalumab, either alone or in conjunction with chemotherapy (n=4 ICI and n=27 ICI+chemo). Pre-treatment samples were provided by The Translational Immunology Laboratory at the University of Sydney. The cohort consisted of 18 males and 13 females, with ages ranging from 56 to 83. Median progression-free survival (PFS) was 11.3 months (95% CI: 6.8 - NR). Responders (n=14) were defined as patients that had not progressed at 12 months post therapy, while non-responders (n=17) had progressed earlier than 12 months. Immune cell populations in responders and non-responders were separately correlated with the circulating glycoproteome, and the resulting correlation maps were compared within glycan-specific changes.Results Correlation map differences were observed across the glycoproteome, and glycan specific ratios of Hexose, HexNACs, Fucose, and Sialic Acid monomers were increased or decreased in Helper T cell, Cytotoxic T cell, and B cell markers. In particular, monomer frequencies of Immunoglobulin G displayed strong differences in Hexose and HexNAC frequencies ( figure 1), with Hexose correlations increased in non-responder’s helper T cell markers and decreased in responder’s B-cell markers. Also, IgG HexNAC monomer increases were associated with helper T cell markers in responders.Conclusions Novel biological mechanisms were uncovered by comparing immune biomarkers across cell populations and circulating glycoproteins. Here, responders and non-responders to ICI therapy displayed varying associations between glycopeptide biomarkers and proteins expressed in various immune cell populations. This suggests a deeper connection in the immune mechanisms controlling tumor progression than has previously been described.Ethics Approval The study was approved by The University of Sydney Ethics Board, approval number X18-0525 & 2019/ETH08954.Abstract 741 Figure 1Comparison of correlation maps between glycan monomer ratios at specific immunoglobulin sites and CyTOF features