Opposing Natural Killer and Macrophage Associations Are Masked Within a CD16/IL-15/IL-15RA Composite Score in Metastatic Urothelial Carcinoma

Programmed death-ligand 1 (PD-L1) poorly predicts immunotherapy benefit in urothelial carcinoma. Avelumab retains an Fc region capable of antibody-dependent cellular cytotoxicity (ADCC), prompting a proposed composite biomarker of CD16, interleukin-15 (IL-15), and IL-15RA. We assessed its construct validity. We built a transcriptomic surrogate in IMvigor210 (348 patients with metastatic urothelial carcinoma treated with atezolizumab, an effector-silenced anti-PD-L1 antibody) and analyzed overall survival with cohort-stratified Cox regression, decomposing the composite against natural killer (NK) cell and macrophage signatures. Among 232 deaths, the composite was not associated with survival (HR 1.03, p = 0.64), whereas tumor mutational burden retained its expected association (HR 0.75). Analyzed separately, the NK signal was protective (HR 0.83), and the macrophage signal was uninformative (HR 1.04); modeled jointly, both strengthened in opposite directions (NK HR 0.71, p = 0.0001; macrophage HR 1.29, p = 0.002). Removing CD16, but not either IL-15 component, reduced the composite’s correlation with macrophage content, and MCP-counter deconvolution reproduced the opposing associations. The composite reads null because its compartments carry opposing associations that mask one another, not because it is specific for ADCC. CD16 should be replaced with NK-restricted markers, and ADCC-competency scores must add value beyond NK abundance.