Establishing a whole blood CD4+ T cell immunity measurement to predict response to anti-PD-1

Abstract

Background Biomarkers that can accurately predict the efficacy of immune checkpoint inhibitors (ICIs) against programmed death 1 (PD-1) ligand in cancer immunotherapy are urgently needed. We have previously reported a novel formula that predicts the response to treatment with second-line nivolumab with high sensitivity and specificity in patients with non-small cell lung cancer (NSCLC) previously treated with chemotherapy. The formula was based on the percentages of CD62LlowCD4+ T cells (effector T cells; %Teff) and CD4+CD25+FOXP3+ T cells (regulatory T cells; %Treg) in the peripheral blood before treatment estimated using the peripheral blood mononuclear cell (PBMC) method. Here, we investigated the applicability of the formula (K-index) to predict the response to treatment with another ICI to expand its clinical applicability. Furthermore, we developed a simpler assay method based on whole blood (WB) samples to overcome the limitations of the PBMC method, such as technical difficulties, in obtaining the K-index. Methods The K-index was evaluated using the PBMC method in 59 patients with NSCLC who received first-line pembrolizumab treatment. We also assessed the K-index using the WB method and estimated the correlation between the measurements obtained using both methods in 76 patients with lung cancer. Results This formula consistently predicted the response to first-line pembrolizumab therapy in patients with NSCLC. The WB method correlated well with the PBMC method to obtain %Teff, %Treg, and the formula value. The WB method showed high repeatability (coefficient of variation, < 10%). The data obtained using WB samples collected in tubes containing either heparin or EDTA-2K and stored at room temperature (18–24 °C) for one day after blood sampling did not differ. Additionally, the performance of the WB method was consistent in different flow cytometry instruments. Conclusions The K-index successfully predicted the response to first-line therapy with pembrolizumab, as reported earlier for the second-line therapy with nivolumab in patients with NSCLC. The WB method established in this study can replace the cumbersome PBMC method in obtaining the K-index. Overall, this study suggests that the K-index can predict the response to anti-PD-1 therapy in various cancers, including NSCLC.

Peripheral CD4 memory T cells predict the efficacy of immune checkpoint inhibitor therapy in patients with non-small cell lung cancer

“…In the tumor microenvironment, CD8 + T cells are associated with the elimination of cancer cells, and it has been reported that tumor-infiltrating CD8 + T cells are associated with the efficacy of ICI therapy 18 , 19 . On the other hand, from the studies investigating peripheral immune cells, several authors have reported the association between CD4 + T cells and the efficacy of ICI therapy 8 – 11 , while the association with CD8 + T cells was also reported 20 , 21 . Furthermore, it was recently reported that CD4 + T cells in the tumor microenvironment are also associated with longer survival after the initiation of ICIs 22 .…”

“…Therefore, investigation for biomarkers that complement tumor PD-L1 expression is underway. Peripheral immune cells are one of them, including lymphocytes 7 – 11 , monocytes 12 , and eosinophils 13 .…”