Profiling Novel Subtypes Of Dendritic Cells And T Cells As Biomarkers For The Efficacy Of Immune Checkpoint Inhibitor Monotherapy

Abstract Background Immune checkpoint inhibitors (ICPIs) have become the new standard treatment regimen for advanced cancer. However, the efficacy of ICPI monotherapy is limited to 10-30%. Although there are several biomarkers for ICPI treatment including PD-L1 expression on tumor cells, MSI status and tumor mutation burden, they are still insufficient. We sought to profile biomarkers based on immunophenotyping analysis via flow cytometry technology by using peripheral blood mononuclear cell (PBMC) samples from patients and found immune cell subpopulations that may be critical indicators of anti-cancer immune treatment response and outcome. Methods Forty-three patients with locally advanced or metastatic cancer who were treated with PD-1/PD-L1 inhibitor monotherapy were enrolled in this study. PBMC samples were collected and monitored before administration of ICPI. Tumor response was evaluated based on RECIST v1.1. Immunophenotyping was performed for all PBMC collected in this study by multi-parametric flow cytometry including panel 1 (CD11c/CD14/CD19/CD56/CD80/CD86/CD274/HLA-ABC/HLA-DR/DAPI) and panel 2 (CD3/CD4/CD8/CD25/CD28/CD62L/CD69/CD152/CD279). T-distributed stochastic neighbor embedding (t-SNE) analysis was performed via FlowJo 10.6. Results We found unique subsets of dendritic cells (CD14low/-CD19-CD11c+HLA-DRlowCD80+CD86-CD274+ referred to as non-classical DC; ncDC) and CD4+CD25+CD62L+ T cells (CD62L+ T) associated with patients with progressive disease (PD; n=24); and CD4+CD28- T cells (CD28- T) associated with patients demonstrating clinical benefit (PR/SD; n=19). The percentage of ncDC was significantly higher in PD patients compared to PR/SD patients (p=0.007). Overall response rate (ORR) was 60.0 % in low ncDC patients (ncDC≤10.6%) and 7.7 % in high ncDC patients. The median progression free survival (PFS) was 195 days for low ncDC patients and 54 days for high ncDC patients (p=0.001). The percentage of CD62L+ T was significantly higher in PD patients compared to PR/SD patients (p=0.001). ORR was 84.2 % in low CD62L+ T patients (CD62L+ T≤4.6%) and 18.5 % in high CD62L+ T patients. The median PFS was 407 days for low CD62L+ T patients and 74 days for high CD62L+ T patients (p=0.006). The ratio of CD28- T/ CD62L+ T was significantly higher in PR/SD patients compared to PD patients (p=0.003). ORR was 84.6 % in high CD28- T/ CD62L+ T patients (CD28- T/ CD62L+ T>5.31) and 30.3 % in low CD28- T/ CD62L+ T patients. The median PFS was not reached for high CD28- T/ CD62L+ T patients and 74 days for low CD28- T/ CD62L+ T patients (p<0.001). Conclusions This study proposed biomarkers based on non-invasive and readily implementable flow cytometry technology. We found subsets of dendritic cells and 2 subsets of T cells significantly correlated to the efficacy of ICPI monotherapy. These subsets can be used as a screening tool for initiating ICPI monotherapy in patients with advanced cancer. Citation Format: Hiroki Nagai, Ganepola A. Ganepola, Jin Lee, Eli Kirshner, Kevin Wood, Thomas Rakowski, Jason Suh, Eleonora Teplinsky, Alysha Insinga, John R. Rutledge, David H. Chang. Profiling novel subtypes of dendritic cells and T cells as biomarkers for the efficacy of immune checkpoint inhibitor monotherapy [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 3199.