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Abstract 1258: Elevated serum DC-HIL is associated with poor response to immune checkpoint inhibitors (ICI) in metastatic renal cell carcinoma (mRCC)


 ICI therapy has shown unprecedented clinical outcomes in mRCC patients, but durable responses have been limited by innate (never respond initially) and acquired resistance (initially respond but eventually develop cancer progression). Establishment of predictive biomarkers for response to ICI maximizes the therapeutic benefit. Since no such marker exists, we investigated DC-HIL/GPNMB as a possibility because we detected DC-HIL to be elevated in blood of patients with metastasis, as both a receptor on myeloid-derived suppressor cells (MDSC) and as a soluble form (sDC-HIL); and found DC-HIL to be relevant to ICI resistance in mice. We studied 27 mRCC patients treated with combination ICI (Ab to PD1/PDL1/CTLA4) and assessed tumor response (by RECIST) at 12 wk after therapy. Blood was collected before and after treatment and assayed by FACS for expression of DC-HIL and PDL1 on CD14+HLA-DRno/lo monocytic (mMDSC) and CD15+CD11b+ granulocytic MDSC (gMDSC). T-cell suppressor function was assayed by cell culture. We showed both MDSC subsets to express DC-HIL predominantly over PDL1. We also showed mMDSC to be more potent T-cell suppressors than gMDSC (85% vs. 58% suppression, p=0.012) and to also be more dependent on DC-HIL for such suppression (56% vs. 15% restoration of T-cell function after adding DC-HIL mAb, p=0.013). However, there was no significant difference in % DC-HIL+MDSC/PBMC between ICI responders and non-responders (p=0.15). We next examined the relationship between tumor response (at 12 wk) and blood sDC-HIL (by ELISA) in 31 mRCC patients. At baseline, non-responders (n=10) had a significantly higher sDC-HIL than responders (n=21) (14 ± 2.4 vs. 10 ± 4.6 ng/ml, p=0.004), but no difference in blood PDL1 or VEGF. Among initial responders (n=22), 50% maintained a positive response while the other half acquired resistance after 20 wk. Among initial non-responders (n=9), 77% never responded while 22% responded positively after 20 wk. We then analyzed changes over time in sDC-HIL levels after treatment (up to 60 wks) in individuals. Patients who responded positively to ICI at treatment inception and through 40 wk maintained blood sDC-HIL at levels lower than the median for all positive responders. Initial responders who acquired resistance (9 out of 11 patients) had low blood sDC-HIL that rose during cancer progression. All constant non-responders (n=7) had high blood sDC-HIL that remained high during the study. To our surprise, the 2 initial non-responders who responded positively after 20-40 wk of ICI displayed an abrupt rise in blood sDC-HIL during their positive response. Our results indicate blood sDC-HIL as a promising biomarker for prognosticating response to ICI in mRCC patients.
 Citation Format: Jin-Sung Chung, Vijay Ramani, Ponciano D. Cruz, Hans J. Hammers, Kiyoshi Ariizumi. Elevated serum DC-HIL is associated with poor response to immune checkpoint inhibitors (ICI) in metastatic renal cell carcinoma (mRCC) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 1258.