Yohei Nose1,2, Takuro Saito3,4, Kei Yamamoto1,2, Kotaro Yamashita2, Koji Tanaka2, Kazuyoshi Yamamoto2, Tomoki Makino2, Tsuyoshi Takahashi2, Atsunari Kawashima1,5, Miya Haruna1,6, Michinari Hirata1,6, Azumi Ueyama1,6, Kota Iwahori1, Taroh Satoh2, Yukinori Kurokawa2, Hidetoshi Eguchi2, Yuichiro Doki2, Hisashi Wada1,2. 1. Department of Clinical Research in Tumor Immunology, Graduate School of Medicine, Osaka University, Suita, Osaka, Japan. 2. Department of Gastroenterological Surgery, Graduate School of Medicine, Osaka University, 2-2 Yamada-oka, Suita City, Osaka, 565-0871, Japan. 3. Department of Clinical Research in Tumor Immunology, Graduate School of Medicine, Osaka University, Suita, Osaka, Japan. tsaito@gesurg.med.osaka-u.ac.jp. 4. Department of Gastroenterological Surgery, Graduate School of Medicine, Osaka University, 2-2 Yamada-oka, Suita City, Osaka, 565-0871, Japan. tsaito@gesurg.med.osaka-u.ac.jp. 5. Department of Urology, Graduate School of Medicine, Osaka University, Suita, Osaka, Japan. 6. Laboratory for Innovative Therapy Research, Shionogi & Co., Ltd, Toyonaka, Osaka, Japan.
Abstract
BACKGROUND: Immune checkpoint inhibitors (ICIs) have revolutionized cancer treatment. Since clinical benefits are limited to a subset of patients, we aimed to identify peripheral blood biomarkers that predict the efficacy of the anti-programmed cell death protein 1 (PD-1) antibody (nivolumab) in patients with gastric cancer. METHODS: We collected peripheral blood samples from gastric cancer patients (n = 29) before and after treatment with nivolumab and investigated the relationship between the frequency of surface or intracellular markers among nivolumab-binding PD-1+CD8+ T cells and treatment responses using multicolor flow cytometry. The tumors, lymph nodes, and peripheral blood of gastric cancer patients who underwent gastrectomy following nivolumab treatment were collected, and nivolumab-binding PD-1+CD8+ T cells in these tissue samples were characterized. RESULTS: Patients with a high frequency of CD103 among PD-1+CD8+ T cells in peripheral blood 2 weeks after the start of treatment had significantly better progression-free survival than the low group (P = 0.032). This CD103+PD-1+CD8+ T cell population mainly consisted of central memory T cells, showing the high expression of Ki-67 and few cytotoxic granules. In contrast, effector memory T cells were more frequently observed among CD103+PD-1+CD8+ T cells in tumors, which implied a change in the differentiated status of central memory T cells in lymph nodes and peripheral blood to effector memory T cells in tumors during the treatment with ICIs. CONCLUSIONS: A high frequency of CD103 among PD-1+CD8+ T cells 2 weeks after nivolumab treatment in patients with advanced gastric cancer may be a useful biomarker for predicting the efficacy of anti-PD-1 therapy.
BACKGROUND: Immune checkpoint inhibitors (ICIs) have revolutionized cancer treatment. Since clinical benefits are limited to a subset of patients, we aimed to identify peripheral blood biomarkers that predict the efficacy of the anti-programmed cell death protein 1 (PD-1) antibody (nivolumab) in patients with gastric cancer. METHODS: We collected peripheral blood samples from gastric cancer patients (n = 29) before and after treatment with nivolumab and investigated the relationship between the frequency of surface or intracellular markers among nivolumab-binding PD-1+CD8+ T cells and treatment responses using multicolor flow cytometry. The tumors, lymph nodes, and peripheral blood of gastric cancer patients who underwent gastrectomy following nivolumab treatment were collected, and nivolumab-binding PD-1+CD8+ T cells in these tissue samples were characterized. RESULTS: Patients with a high frequency of CD103 among PD-1+CD8+ T cells in peripheral blood 2 weeks after the start of treatment had significantly better progression-free survival than the low group (P = 0.032). This CD103+PD-1+CD8+ T cell population mainly consisted of central memory T cells, showing the high expression of Ki-67 and few cytotoxic granules. In contrast, effector memory T cells were more frequently observed among CD103+PD-1+CD8+ T cells in tumors, which implied a change in the differentiated status of central memory T cells in lymph nodes and peripheral blood to effector memory T cells in tumors during the treatment with ICIs. CONCLUSIONS: A high frequency of CD103 among PD-1+CD8+ T cells 2 weeks after nivolumab treatment in patients with advanced gastric cancer may be a useful biomarker for predicting the efficacy of anti-PD-1 therapy.
Authors: Alice O Kamphorst; Rathi N Pillai; Shu Yang; Tahseen H Nasti; Rama S Akondy; Andreas Wieland; Gabriel L Sica; Ke Yu; Lydia Koenig; Nikita T Patel; Madhusmita Behera; Hong Wu; Megan McCausland; Zhengjia Chen; Chao Zhang; Fadlo R Khuri; Taofeek K Owonikoko; Rafi Ahmed; Suresh S Ramalingam Journal: Proc Natl Acad Sci U S A Date: 2017-04-26 Impact factor: 11.205
Authors: Janis M Taube; Alison Klein; Julie R Brahmer; Haiying Xu; Xiaoyu Pan; Jung H Kim; Lieping Chen; Drew M Pardoll; Suzanne L Topalian; Robert A Anders Journal: Clin Cancer Res Date: 2014-04-08 Impact factor: 12.531
Authors: Suzanne L Topalian; F Stephen Hodi; Julie R Brahmer; Scott N Gettinger; David C Smith; David F McDermott; John D Powderly; Richard D Carvajal; Jeffrey A Sosman; Michael B Atkins; Philip D Leming; David R Spigel; Scott J Antonia; Leora Horn; Charles G Drake; Drew M Pardoll; Lieping Chen; William H Sharfman; Robert A Anders; Janis M Taube; Tracee L McMiller; Haiying Xu; Alan J Korman; Maria Jure-Kunkel; Shruti Agrawal; Daniel McDonald; Georgia D Kollia; Ashok Gupta; Jon M Wigginton; Mario Sznol Journal: N Engl J Med Date: 2012-06-02 Impact factor: 91.245