B7-H3 Negatively Modulates CTL-Mediated Cancer Immunity

• Published in: Clinical cancer research Vol. 24; no. 11; pp. 2653 - 2664
• Main Authors: Yonesaka, Kimio, Haratani, Koji, Takamura, Shiki, Sakai, Hitomi, Kato, Ryoji, Takegawa, Naoki, Takahama, Takayuki, Tanaka, Kaoru, Hayashi, Hidetoshi, Takeda, Masayuki, Kato, Sigeki, Maenishi, Osamu, Sakai, Kazuko, Chiba, Yasutaka, Okabe, Takafumi, Kudo, Keita, Hasegawa, Yoshikazu, Kaneda, Hiroyasu, Yamato, Michiko, Hirotani, Kenji, Miyazawa, Masaaki, Nishio, Kazuto, Nakagawa, Kazuhiko
• Format: Journal Article
• Language: English
• Published: United States American Association for Cancer Research Inc 01.06.2018
• Subjects: Aged; Aged, 80 and over; Animals; Anticancer properties; Antineoplastic Agents, Immunological - pharmacology; Antineoplastic Agents, Immunological - therapeutic use; Antineoplastic Combined Chemotherapy Protocols - adverse effects; Antineoplastic Combined Chemotherapy Protocols - therapeutic use; Antitumor activity; Apoptosis; B7 antigen; B7 Antigens - metabolism; B7-H1 Antigen - antagonists & inhibitors; B7-H1 Antigen - metabolism; Biomarkers, Tumor; Blocking antibodies; Cancer; CD8 antigen; Cell survival; Cytotoxicity; Disease Models, Animal; Drug Resistance, Neoplasm; Effectiveness; Experimental design; Female; Flow cytometry; Humans; Immune checkpoint; Immunity; Immunomodulation; Immunosurveillance; Immunotherapy; Lung cancer; Lymphocytes; Lymphocytes T; Male; Mice; Middle Aged; Molecular chains; Molecular Targeted Therapy; Mutation; Neoplasms - immunology; Neoplasms - metabolism; Neoplasms - pathology; Neoplasms - therapy; Non-small cell lung carcinoma; PD-1 protein; PD-L1 protein; Prognosis; T-Lymphocytes, Cytotoxic - immunology; T-Lymphocytes, Cytotoxic - metabolism; Therapy; Treatment Outcome; Tumor cells; Tumor-infiltrating lymphocytes; Tumors; Xenograft Model Antitumor Assays
• ISSN: 1078-0432; 1557-3265; 1557-3265
• DOI: 10.1158/1078-0432.CCR-17-2852

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.