CD24, not CD47, negatively impacts upon response to PD-1/L1 inhibitors in non-small cell lung cancer with PD-L1 TPS <50.

CD24, a heavily glycosylated glycosylphosphatidylinositol-anchored surface protein, inhibits phagocytosis as potently as CD47. The relationship between such anti-phagocytic factors and immune-response with immune-checkpoint inhibitors (ICI) remains unexplored. We evaluated CD24 and CD47 tumor proportion scores (TPS) in 68 of the 106 patients with advanced non-small cell lung cancer who participated in a prospective observational study of ICI treatment. We also explored the impact of CD24 TPS and CD47 TPS on ICI efficacy and serum cytokine changes. CD24 positivity (TPS ≥1) was negatively associated with progression free survival of ICI when PD-L1 TPS <50 (median PFS; 37 vs. 127 days, P=0.033), but there was no association when PD-L1 TPS ≥50 (median PFS; 494 vs. 144 days, P=0.168). CD24 positivity was also related to significantly higher increase of CCL2 from baseline to 4-6 weeks later, and such increase was notably observed only when PD-L1 TPS <50 (P=0.0004). CCL2 increase after ICI initiation was negatively predictive for survival after initiation of ICI (median survival time; not reached vs. 233 days, P=0.028). CD47 TPS high (≥60) significantly suppressed the increase in VEGF-A, D and PDGF-AB/BB after ICI initiation. There was no association, however, between CD47 tumor expression and the efficacy of ICI. In conclusion, CD24, not CD47, is a candidate negative predictive marker of ICI in advanced, non-small cell lung cancer with PD-L1 TPS <50. Tumor expression of both CD24 and CD47 was associated with changes in factors related to monocytes and angiogenesis after ICI initiation.