Yonesaka et al. found that the expression of B7-H3 (a B7-family member with an unknown ligand) in human non-small cell lung cancer correlated with decreased CD8+ T cell tumor infiltration, non-response to anti-PD-1 therapy, and shorter progression-free survival. In syngeneic mouse models of pancreatic and lung cancers, treatment with anti-B7-H3 antibody delayed tumor growth by increasing CD8+ T cell effector function and tumor infiltration. Dual PD-L1/B7-H3 blockade was well-tolerated and inhibited tumor growth more effectively than either monotherapy.

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 to a single blocking antibody, dual blockade of B7-H3 and PD-L1 enhanced the anti-tumor 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.

Author Info: (1) Department of Medical Oncology, Kindai University Faculty of Medicine yonesaka2002@yahoo.co.jp. (2) Department of Medical Oncology, Kindai University Faculty of Medicine. (3) Department of Immunology

Author Info: (1) Department of Medical Oncology, Kindai University Faculty of Medicine yonesaka2002@yahoo.co.jp. (2) Department of Medical Oncology, Kindai University Faculty of Medicine. (3) Department of Immunology, Kindai University Faculty of Medicine. (4) Department of Medical Oncology, Kindai University Faculty of Medicine. (5) Department of Medical Oncology, Kindai University Faculty of Medicine. (6) Department of Medical Oncology, Kindai University Faculty of Medicine. (7) Department of Medical Oncology, Kindai University Faculty of Medicine. (8) Department of Medical Oncology, Kindai University faculty of Medicine. (9) Department of Medical Oncology, Kindai University Faculty of Medicine. (10) Department of Medical Oncology, Kindai University Faculty of Medicine. (11) Kindai University Faculty of Medicine. (12) Department of Pathology, Kindai University Faculty of Medicine. (13) Department of Genome Biology, Kinki University Faculty of Medicine. (14) Department of Environmental Medicine and Behavioral Science, Kinki University School of Medicine. (15) oncology, Kindai University Sakai Hospital. (16) Department of Medical Oncology, Kinki University Faculty of Medicine. (17) Izumi Municipal Hospital. (18) Department of Medical Oncology, Kindai University Faculty of Medicine. (19) Biologics & Immuno-Oncology Laboratories, Daiichi Sankyo Co., Ltd. (20) R&D division, Daiichi Sankyo Pharmaceutical Development. (21) Faculty of Medicine, Kindai University. (22) Department of Genome Biology, Kindai University Faculty of Medicine. (23) Department of Medical Oncology, Kindai University.

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