Anti-PD-1 Therapy Response Predicted by the Combination of Exosomal PD-L1 and CD28

Background: Anti-PD-1 therapy has been approved for cancer treatment. However, the response rate is unsatisfactory. The expression of PD-L1 in tumor tissues affected by chemotherapy, radiotherapy, and activity of signal transduction pathways, is unreliable to predict the treatment response. Recent studies suggested that exosomal PD-L1 not only exerts immunosuppressive effects but also plays a significant role in the development of tumor microenvironment. Thus, the present study aimed to investigate exosomal PD-L1 in improving its predictive value and treatment efficacy. Methods: A total of 44 patients with several types of advanced tumors, treated by anti-PD-1 therapy, were enrolled. Exosomes were collected and purified from plasma using the exosome isolation kit. The exosomal PD-L1 and exosomal PD-1 were detected by ELISA. The cytokines were measured by the MILLIPLEX magnetic bead assay. Results: Compared to the responders, exosomal PD-L1 and exosomal PD-1 of the non-responders were significantly higher than those of the responders (P=0.010 and P=0.022, respectively) before the treatment. Concurrently, exosomal PD-L1, exosomal PD-1, and tumor burden decreased when the therapy was effective. Also, the baseline expression of CD28 was higher in the responders than non-responders (P=0.005). Univariate and multivariate analysis validated with 1000 times bootstrapping suggested that high exosomal PD-L1 and low CD28 expression were negative factors for progression-free survival (PFS) in patients who underwent anti-PD-1 treatment. The combination of exosomal PD-L1 and CD28 obtained more area under the curve (AUC) of receiver operating characteristic (ROC) (AUC 0.850 vs. 0.784 vs. 0.678) and showed a higher probability without progression via nomograph. Conclusions: Baseline low levels of exosomal PD-L1 and high expression of CD28 screened out the potential beneficiary populations of anti-PD-1 therapy in a variety of solid tumors. These findings suggested that the expression of exosomal PD-L1 and CD28 could serve as the predictive biomarkers for clinical responses to anti-PD-1 treatment. Funding Statement: This study was funded by The National Key Research and Development Program of China (NO.2017YFC1308900); National Science and Technology Major Project of the Ministry of Science and Technology of China (No. 2017ZX09304025); National Natural Science Foundation of China (NO.81602098, NO.31770963); The Key Research and Development Program of Liaoning Province (NO.2018225060); Science and Technology Plan Project of Liaoning Province (NO.2016007010). Declaration of Interests: All authors have declared no conflicts of interest. Ethics Approval Statement: The study was approved by the local Ethics Committee and all the procedures were conducted in accordance with the ethical principles of China Medical University (Scientific Ethics NO. 2019-142-2). Clinical information of all patients was retrieved from the Hospital Information System.