Abstract
AbstractBACKGROUNDNivolumab paved a new way in the treatment of patients with recurrent or metastatic (RM) head and neck squamous cell carcinoma (RM-HNSCC). However, the limited rates of long-term survivors (< 20%) demand a robust prognostic biomarker. This nationwide multi-centric prospective study aimed to identify a plasma exosome (PEX) mRNA signature, which serves as a companion diagnostic of nivolumab and provides a biological clue to develop effective therapies for a majority of non-survivors.METHODSPre-treatment plasmas (N= 104) of RM-HNSCC patients were subjected to comprehensive PEX mRNA analyses for prognostic marker discovery and validation. In parallel, paired treatment-naïve tumor and plasma samples (N= 20) were assayed to elucidate biological implications of the PEX mRNA signature.RESULTSA combination of 6 candidate PEX mRNAs plus neutrophil-to-lymphocyte ratio precisely distinguished non-survivors from >2-year survivors (2-year OS; 0% vs 57.7%;P= 0.000124) with a high hazard ratio of 2.878 (95% CI 1.639-5.055;P= 0.0002348). In paired samples, PEXHLA-EmRNA (a non-survivor-predicting marker) was positively corelated with overexpression of HLA-E protein (P= 0.0191) and the dense population of tumor-infiltrating NK cells (P= 0.024) in the corresponding tumor, suggesting the HLA-E-NKG2A immune checkpoint may inhibit the antitumor effect of PD-1blockade in patients with high PEXHLA-EmRNA.CONCLUSIONThe PEX mRNA signature could be useful as a companion diagnostic of nivolumab. The combination of an anti-NKG2A antibody (i.e., monalizumab) and nivolumab may serve as a treatment option for non-survivors predicted by a RT-qPCR-based pre-treatment measurement of PEX mRNAs.TRIAL REGISTRATIONThis study is registered to the UMIN Clinical Trial Registry: UMIN000037029.FUNDINGThis study is partly funded by JSPS KAKENHI (Grant number JP 21436707 to MM) and Sota memorial fund to MM. PEXmRNA analyses were conducted by Showa Denko America Materials. CReS Kyushu organized sample collection and transfer, and conducted clinical data management with funding provided by Ono and Bristol-Myers Squibb.Graphical abstract
Publisher
Cold Spring Harbor Laboratory