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

• Published in: BMC cancer Vol. 22; no. 1; pp. 1325 - 10
• Main Authors: Yamaguchi, Ou, Atarashi, Kazuyuki, Yoshimura, Kenichi, Shiono, Ayako, Mouri, Atsuhito, Nishihara, Fuyumi, Miura, Yu, Hashimoto, Kosuke, Miyamoto, Yoshiaki, Uga, Hitoshi, Seki, Nobuo, Matsushima, Tomoko, Kikukawa, Norihiro, Kobayashi, Kunihiko, Kaira, Kyoichi, Kagamu, Hiroshi
• Format: Journal Article
• Language: English
• Published: England BioMed Central Ltd 17.12.2022; BioMed Central; BMC
• Subjects: Analysis; Apoptosis; B7-H1 Antigen - metabolism; Biological markers; Biomarkers; Biopsy; Blood; Cancer; Cancer immunotherapy; Carcinoma, Non-Small-Cell Lung - metabolism; Care and treatment; CD25 antigen; CD4 antigen; Chemotherapy; Diagnosis; Dosage and administration; Effector CD4+ T cells; Effector cells; Flow cytometry; Foxp3 protein; Heparin; Humans; Immune checkpoint inhibitors; Immunoregulation; Immunotherapy; Informed consent; Leukocytes, Mononuclear - metabolism; Lung cancer; Lung cancer, Non-small cell; Lung Neoplasms - metabolism; Lymphocytes; Lymphocytes T; Medical examination; Monoclonal antibodies; Nitrogen; Nivolumab - pharmacology; Nivolumab - therapeutic use; Non-small cell lung cancer; Non-small cell lung carcinoma; Patient outcomes; Patients; PD-1 blockade therapy; PD-1 protein; Pembrolizumab; Peripheral blood mononuclear cells; Programmed Cell Death 1 Receptor - metabolism; Receptor antibodies; Small cell lung carcinoma; Software; T-Lymphocytes, Regulatory - metabolism; Tumors; Japan; United States > US; Biomarkers; Flow cytometry; PD-1 blockade therapy; Effector CD4+ T cells; Non-small cell lung cancer
• DOI: 10.1186/s12885-022-10445-2
• ISSN: 1471-2407

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 CD62L CD4 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. 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. 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. 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.