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
Oliver Hoffmann, Sebastian Wormland, Ann‐Kathrin Bittner, Monika Collenburg, Peter A. Horn, Rainer Kimmig, Sabine Kasimir‐Bauer, Vera Rebmann
Abstract
Abstract 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.