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Peer-reviewedCC BY 4.0International Journal of Molecular Sciences

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

  • Erkut Demirciler1
  • Faruk Recep Özalp2
  1. 1Department of Medical Oncology, Izmir City Hospital, Izmir 35540, Turkey
  2. 2Department of Medical Oncology, Osmaniye Education and Research Hospital, Osmaniye 80000, Turkey
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Abstract

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.

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Cite

BibTeXRIS
BibTeX
@article{demirciler2026opposing,
  title = {{Opposing Natural Killer and Macrophage Associations Are Masked Within a CD16/IL-15/IL-15RA Composite Score in Metastatic Urothelial Carcinoma}},
  author = {Erkut Demirciler and Faruk Recep Özalp},
  journal = {International Journal of Molecular Sciences},
  year = {2026},
  month = oct,
  doi = {10.3390/ijms27208943},
  url = {https://www.mdpi.com/1422-0067/27/20/8943},
  note = {CC BY 4.0},
}
RIS
TY  - JOUR
TI  - Opposing Natural Killer and Macrophage Associations Are Masked Within a CD16/IL-15/IL-15RA Composite Score in Metastatic Urothelial Carcinoma
AU  - Erkut Demirciler
AU  - Faruk Recep Özalp
PY  - 2026
DA  - 2026/10/09
JO  - International Journal of Molecular Sciences
DO  - 10.3390/ijms27208943
UR  - https://www.mdpi.com/1422-0067/27/20/8943
AB  - 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.
SN  - 1422-0067
ER  -