B7-H3 Negatively Modulates CTL-Mediated Cancer Immunity
| Autor: | Koji Haratani, Yasutaka Chiba, Shiki Takamura, Takafumi Okabe, Kenji Hirotani, Hiroyasu Kaneda, Michiko Yamato, Kaoru Tanaka, Shigeki Kato, Kazuhiko Nakagawa, Kazuto Nishio, Hidetoshi Hayashi, Yoshikazu Hasegawa, Masayuki Takeda, Kazuko Sakai, Kimio Yonesaka, Masaaki Miyazawa, Osamu Maenishi, Ryoji Kato, Naoki Takegawa, Takayuki Takahama, Hitomi Sakai, Keita Kudo |
|---|---|
| Rok vydání: | 2018 |
| Předmět: |
Male
0301 basic medicine Cancer Research B7 Antigens medicine.medical_treatment B7-H1 Antigen Immunomodulation Mice 03 medical and health sciences Antineoplastic Agents Immunological 0302 clinical medicine Neoplasms Antineoplastic Combined Chemotherapy Protocols Blocking antibody Biomarkers Tumor medicine Animals Humans Neoplasm Molecular Targeted Therapy Aged Aged 80 and over Effector business.industry Cancer Immunotherapy Middle Aged Prognosis medicine.disease Xenograft Model Antitumor Assays Blockade Disease Models Animal CTL Treatment Outcome 030104 developmental biology Oncology Drug Resistance Neoplasm 030220 oncology & carcinogenesis Mutation Cancer research Female business CD8 T-Lymphocytes Cytotoxic |
| Zdroj: | Clinical Cancer Research. 24:2653-2664 |
| ISSN: | 1557-3265 1078-0432 |
| DOI: | 10.1158/1078-0432.ccr-17-2852 |
| Popis: | Purpose: Anti-programmed-death-1 (PD-1) immunotherapy improves survival in non–small cell lung cancer (NSCLC), but some cases are refractory to treatment, thereby requiring alternative strategies. B7-H3, an immune-checkpoint molecule, is expressed in various malignancies. To our knowledge, this study is the first to evaluate B7-H3 expression in NSCLCs treated with anti-PD-1 therapy and the therapeutic potential of a combination of anti-PD-1 therapy and B7-H3 targeting. Experimental Design: B7-H3 expression was evaluated immunohistochemically in patients with NSCLC (n = 82), and its relationship with responsiveness to anti-PD-1 therapy and CD8+ tumor-infiltrating lymphocytes (TILs) was analyzed. The antitumor efficacy of dual anti-B7-H3 and anti-programmed death ligand-1 (PD-L1) antibody therapy was evaluated using a syngeneic murine cancer model. T-cell numbers and functions were analyzed by flow cytometry. Results: B7-H3 expression was evident in 74% of NSCLCs and was correlated critically with nonresponsiveness to anti-PD-1 immunotherapy. A small number of CD8+ TILs was observed as a subpopulation with PD-L1 tumor proportion score less than 50%, whereas CD8+ TILs were still abundant in tumors not expressing B7-H3. Anti-B7-H3 blockade showed antitumor efficacy accompanied with an increased number of CD8+ TILs and recovery of effector function. CD8+ T-cell depletion negated antitumor efficacy induced by B7-H3 blockade, indicating that improved antitumor immunity is mediated by CD8+ T cells. Compared with a single blocking antibody, dual blockade of B7-H3 and PD-L1 enhanced the antitumor reaction. Conclusions: B7-H3 expressed on tumor cells potentially circumvents CD8+-T-cell–mediated immune surveillance. Anti-B7-H3 immunotherapy combined with anti-PD-1/PD-L1 antibody therapy is a promising approach for B7-H3–expressing NSCLCs. Clin Cancer Res; 24(11); 2653–64. ©2018 AACR. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|