B7 H3 Negatively Modulates CTL Mediated Cancer Immunity
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. (c)2018 AACR.
Clinical Cancer Research