Programmed death receptor ligand-2 (PD-L2) bearing extracellular vesicles as a new biomarker to identify early triple-negative breast cancer patients at high risk for relapse

PURPOSE: Based on the tumor-promoting features of extracellular vesicles (EV) and PD-L1/2-bearing EV subpopulations (PD-L1/2(EV)), we evaluated their potential as surrogate markers for disease progression or eligibility criteria for PD-1 immune checkpoint inhibition (ICI) approaches in early triple-negative breast cancer (TNBC). METHODS: After enrichment of EV from plasma samples of 56 patients before and 50 after chemotherapy (CT), we determined levels of EV particle number and PD-L1/2(EV) by nanoparticle tracking analysis or ELISA and associated the results with clinical status/outcome and the presence of distinct circulating tumor cells (CTC) subpopulations. RESULTS: Compared to healthy controls, patients had a tenfold higher EV concentration and significantly elevated PD L2(EV) but not PD L1(EV) levels. The most important clinical implications were found for PD-L2(EV). High PD-L2(EV) levels were associated with a significantly reduced 3-year progression-free and overall survival (PFS and OS). A loss of PD-L2(EV) after CT was significantly more prominent in patients achieving pathological complete response (pCR). Increased pre-CT PD-L2(EV) levels were found in patients having NOTCH1-positive or ERBB3-positive CTC. The presence of ERBB3-positive CTC combined with high pre-CT PD-L2(EV) resulted in a shorter PFS. CONCLUSION: This study highlights PD L2(EV) as a promising biomarker for risk assessment of TNBC patients and represents the basic for additional studies introducing PD-L2(EV) as an eligibility criterion for PD-1 ICI approaches. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s00432-022-03980-9.