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Among currently available treatments for non-small cell lung carcinoma (NSCLC), immune checkpoint inhibitors (ICI) have produced the most significant improvement in survival rates. However, this best treatment benefits only a minority of treated cases (10-20 percent), with >80 percent of patients primarily resistant to this therapy. Our subject is to understand resistance mechanisms to immunotherapy with immune checkpoint inhibitor and to identify biomarkers distinguishing responders vs. non-responders. In this funding period, we examined whether NSCLC patients express soluble DC-HIL (sDC-HIL) protein in the blood and whether high blood levels of sDC-HIL correlate with poor response to ICI therapy. Blood sDC-HIL at pretreatment (week 0) was measured and analyzed for correlation with cancer progression. Responders to ICI therapy displayed sDC-HIL at levels no different from healthy donors. By contrast, non-responders had significantly higher sDC-HIL levels (p<0.0001 by Mann-Whitney U test). Among non-responders, the percent change in sDC-HIL levels in the first 6 weeks after treatment correlated significantly with % change in tumor size (p<0.00001). These results indicate that blood sDC-HIL levels strongly associate with cancer progression and poor outcomes. Our studies demonstrate DC-HILs negative influence on ICI therapy, highlighting its potential as a blood biomarker to predict treatment responsiveness and clinical benefit.