870 Characterization of GDF-15 expression patterns in renal cell carcinoma

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Background Growth and Differentiation Factor 15 (GDF-15) is a secreted cytokine in the TGF-beta superfamily that is highly expressed in the placenta during pregnancy and in certain solid tumors. In cancer, it is thought to help mediate immune escape and possibly resistance to anti-PD-1/L1 therapies by limiting immune cell activation and T cell infiltration. An early phase clinical trial suggests that blocking GDF-15 may be an effective way to reinvigorate anti-tumor immune responses. Here, we aimed to characterize GDF-15 expression patterns in renal cell carcinoma (RCC) and how they relate to clinicopathologic features of disease.Methods We used quantitative immunofluorescence (qIF) to measure GDF-15 expression (Sigma-Aldrich HPA011191, 1:50) in RCC tissue microarrays (TMAs) encompassing tissue from primary tumors and metastatic sites. Expression levels were correlated with clinicopathologic factors. Additionally, plasma GDF-15 levels were measured in two clear cell RCC (ccRCC) patient cohorts: 13 patients with localized ccRCC undergoing nephrectomy, assessed pre- and post-nephrectomy using the SomaScan 11K Assay; and 21 patients with advanced ccRCC being treated with ipilimumab and nivolumab (ipi+nivo), assessed pre-treatment and prior to cycle 3 using a multiplexed cytokine array (Eve Technologies).Results As assessed by qIF, GDF-15 levels were higher in metastatic tumor specimens relative to matched primary tumors (p=0.02) ( figure 1A). GDF-15 expression was also higher in non-ccRCC compared to ccRCC (p=0.02) (figure 1B). In a patient cohort not limited to immune checkpoint inhibitor (ICI) treatment, higher expression of GDF-15 was associated with worse five-year progression-free (HR=2.7, p=0.002) and overall survival (HR=2.5, p=0.02) (figure 1C-D). However, we did not observe a relationship between GDF-15 levels and response to ICIs (p=0.7) (figure 1E). In patients with localized ccRCC undergoing nephrectomy, circulating plasma GDF-15 levels decreased post-nephrectomy (p=0.004) (figure 2A). Among advanced ccRCC patients undergoing treatment with ipi+nivo, higher plasma GDF-15 prior to treatment was associated with pre-existing cachexia (p=0.02), presence of brain metastases (p=0.006), and an intact primary tumor (i.e., no prior nephrectomy) (p=0.001) (figure 2B-D). Similar to the qIF data, there was not a significant association between plasma GDF-15 levels and response to ipi+nivo (p=0.2) (figure 2E).Conclusion GDF-15 is expressed in the RCC tumor microenvironment, including primary tumors and metastases. Intact primary tumors may be a source of circulating GDF-15, for both localized and advanced disease. GDF-15 expression levels may have prognostic significance in RCC but do not appear to be associated with response to ICIs.Ethics Approval These studies were approved by the Yale Institutional Review Board (IRB #s 0805003787 and 0609001869) and participants gave informed consent as required by the IRB.Abstract 870 Figure 1Abstract 870 Figure 2

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