OX40 and LAG3 are associated with better prognosis in advanced gastric cancer patients treated with anti-programmed death-1 antibody

• Published in: British journal of cancer Vol. 122; no. 10; pp. 1507 - 1517
• Main Authors: Ohmura, Hirofumi, Yamaguchi, Kyoko, Hanamura, Fumiyasu, Ito, Mamoru, Makiyama, Akitaka, Uchino, Keita, Shimokawa, Hozumi, Tamura, Shingo, Esaki, Taito, Mitsugi, Kenji, Shibata, Yoshihiro, Oda, Hisanobu, Tsuchihashi, Kenji, Ariyama, Hiroshi, Kusaba, Hitoshi, Oda, Yoshinao, Akashi, Koichi, Baba, Eishi
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 01-05-2020; Nature Publishing Group
• Subjects: 631/67/1504/1829; 692/53/2422; Adult; Aged; Aged, 80 and over; Antigens, CD - genetics; Apoptosis; Biomedical and Life Sciences; Biomedicine; Cancer Research; CD223 antigen; CD4 antigen; CD4-Positive T-Lymphocytes - drug effects; CD8 antigen; CD8-Positive T-Lymphocytes - drug effects; Cytokines; Drug Resistance; Effector cells; Epidemiology; Female; Flow Cytometry; Gastric cancer; Humans; Immunological memory; Immunoregulation; Lymphocytes; Lymphocytes T; Male; Medical prognosis; Memory cells; Middle Aged; Molecular Medicine; Monoclonal antibodies; Nivolumab - administration & dosage; Nivolumab - adverse effects; Oncology; OX40 Ligand - genetics; PD-1 protein; Peripheral blood; Prognosis; Programmed Cell Death 1 Receptor - antagonists & inhibitors; Programmed Cell Death 1 Receptor - genetics; Programmed Cell Death 1 Receptor - immunology; Progression-Free Survival; Stomach Neoplasms - drug therapy; Stomach Neoplasms - genetics; Stomach Neoplasms - immunology; Stomach Neoplasms - pathology; T-Lymphocytes, Regulatory - drug effects; Targeted cancer therapy; Tumor necrosis factor
• ISSN: 0007-0920; 1532-1827
• DOI: 10.1038/s41416-020-0810-1

Background
Anti-PD-1 monoclonal antibody, nivolumab, has shown efficacy for advanced gastric cancer (AGC). However, the specific immune cell subsets predominantly activated during the period of anti-PD-1 therapy for AGC have not been clarified.
Methods
Peripheral blood of 30 AGC patients treated with nivolumab was prospectively obtained before the initial and second administrations and at the time of progressive disease (PD). The proportions of immune cell subsets and the serum concentrations of cytokines were systematically analysed by flow cytometry. Associations of subsets and serum cytokines with therapeutic effects were evaluated.
Results
After the initial administration, significant increases in activated central/effector memory, activated effector T cells, and activated T-helper 1 subsets were observed. At the time of PD, activated regulatory T cells, LAG3-positive CD4+/CD8+ T cells, and TIM3-positive CD4+/CD8+ T cells increased significantly. Significant positive correlations were shown between progression-free survival and proportions of LAG3-positive CD4+/CD8+ T cells and of OX40-positive CD4+/CD8+ T cells (log-rank
p
 = 0.0008, 0.0003, 0.0035 and 0.0040).
Conclusions
Nivolumab therapy enhances activation of central/effector memory and effector subsets of CD4+/CD8+ T cells. The expression levels of LAG-3 and OX40 on T cells correlated with the efficacy of nivolumab therapy and could be reasonable biomarkers for anti-PD-1 therapy.