864 Delineating the role of growth differentiation Factor 15 (GDF-15) in advanced bladder and upper tract urinary cancers (BC): university of Washington rapid autopsy program (UW-RAP) cohort

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Background GDF-15, a divergent member of the TGF-β superfamily, induces cancer cachexia (CC) and interferes with antitumor immune response. 1–3 The role of GDF-15 and its immunomodulatory effects are not well characterized in BC. This study aims to identify clinicopathologic characteristics, particularly CC, and immunological features in relation to GDF-15 levels using biospecimens from the UW-RAP.Methods For this study, we used matched post-mortem serum (n=17) and tumor samples (n=10) obtained from the UW-RAP cohort of 17 BC patients. We assessed clinicopathologic and anthropometric measurements (radiographic sarcopenia) from the UW-RAP. We dichotomized patients based on CC status within 6 months before death using the international consensus definition. 4 We analyzed circulating levels of 45 cytokines, multi-regional tumor GDF-15 mRNA expression, and immune cell composition using RNA sequencing/CIBERSORTx.5 Our primary objective was determining the relationship between GDF-15 and inflammatory cytokines/immune cells within metastatic sites in patients with/without CC.Results Of the 17 patients, 11/17 (65%) met criteria for CC. Gender, age, smoking history or histology were not associated with CC status. Median circulating log 10GDF-15 levels were 3.84 pg/mL and 4.14 pg/mL in the CC and non-CC group, respectively (p=0.64). A trend towards higher circulating GDF-15 levels was observed in patients who received more lines of systemic therapy (p=0.08). Serum GDF-15 levels correlated with higher IFN-γ (β = 0.49, p = 0.011), IL-1β (β = 0.41, p = 0.047), and IL-13 (β = 0.70, p = 0.038) levels, and specifically in patients with CC, GDF-15 correlated with IFN-γ (β = 0.52, p = 0.048) and IL-4 (β = 0.38, p = 0.011). Higher circulating GDF-15 levels correlated with higher mean tumor GDF-15 mRNA expression in metastasis sites (p=0.007). Tumor GDF-15 expression was highest in lymph nodes metastases (figure 1) and was not significantly different by CC status (p=0.67). Significant downregulation of FAS, CSF3, GMZB, INF-γ, IL-6 and CCL2 mRNA expression were noted in non-CC compared to CC patients. Overall, tumor GDF-15 expression was associated with the presence of naïve B-cells in the tumor microenvironment (p=0.01), but not with other immune cells.Conclusions In this cohort, post-mortem circulating GDF-15 levels were elevated in patients with BC, independent of cachexia status, but appeared higher in heavily pre-treated patients. Tumor GDF-15 expression was similar in both CC and non-CC groups, but particularly elevated in lymph nodes, suggesting organ specificity. Unique cytokine pathways appear to be associated with CC. Tumor GDF-15 expression influences B-cell infiltration of the tumor.References Lerner L, et al. MAP3K11/GDF15 axis is a critical driver of cancer cachexia. J Cachexia Sarcopenia Muscle. 2016;7(4):467–82.Haake M, et al. Tumor-derived GDF-15 blocks LFA-1 dependent T cell recruitment and suppresses responses to anti-PD-1 treatment. Nat Commun. 2023;14(1):4253.Lerner L, et al. Plasma growth differentiation factor 15 is associated with weight loss and mortality in cancer patients. J Cachexia Sarcopenia Muscle. 2015;6(4):317–24.Fearon K, et al. Definition and classification of cancer cachexia: an international consensus. Lancet Oncol. 2011;12(5):489–95.Newman AM, et al. Determining cell type abundance and expression from bulk tissues with digital cytometry. Nat Biotechnol, 2019;37(7):773–782.Ethics Approval This study was approved by the University of Washington Institutional Review Board. Patients with metastatic bladder and upper tract urinary cancers were consented.Abstract 864 Figure 1GDF-15 tumor mRNA expression according to organ metastatic site. Most common metastatic sites included bone, liver, lung, and lymph node. Median tumor GDF-15 levels as measured

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