B7-H3 Negatively Modulates CTL-Mediated Cancer Immunity

Abstract

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. B7-H3 expression was evaluated immunohistochemically in patients with NSCLC ( = 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. 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. 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. .

B7-H3, a checkpoint molecule, as a target for cancer immunotherapy

“…B7-H3 was found to be overexpressed among several kinds of human cancer cells and was correlated with disease deteriorations [13][14][15][16][17][18][19] (Table 2). B7-H3 was recognized as a co-stimulatory molecule for immune reactions such as T cell activation and IFN-γ production [20].…”

Profiling targetable immune checkpoints in osteosarcoma

“…A recent report shows that blockade of B7-H3 decreases tumor size and increases the number of CD8 + tumor infiltrating lymphocytes in syngeneic models of pancreatic cancer and lung cancer. 43 Another report indicates that antibody-mediated inhibition of B7-H3 reduces tumor growth as well as the number of tumor associated macrophages and myeloid derived suppressor cells in genetic 44 The utility of B7-H3 as a therapeutic target is further supported by a recent report using xenograft and allograft models of various carcinomas to demonstrate the efficacy of B7-H3 antibody-drug conjugates (ADCs) to successfully target both tumor cells and tumor associated vasculature, prolong survival, and reduce metastasis. 35 As it pertains to osteosarcoma, our data showing that increased B7-H3 expression correlates with poor survival is consistent with that of Wang et al, collectively indicating that this molecule may be an attractive immunotherapeutic target in this disease.…”

Emerging immunotherapy targets in lung cancer

“…B7-H3 is expressed in 70% to 80% of NSCLC cases. [ 32 , 33 ] High expression of this protein is correlated with smoking history and a shortened overall survival in patients. [ 32 ] Soluble B7-H3 in malignant pleural effusions is a potential biomarker for its correlation with the stage of NSCLC.…”

“…[ 34 ] In addition, B7-H3 is associated with refractoriness to PD-1 antibodies and effective anti-tumor activity by increasing CD8+ T cell infiltration, which was shown in the dual blockade of B7-H3 and PD-1. [ 33 ] Another study also reported that inhibition of B7-H3 could enhance the sensitivity to cisplatin chemotherapy. [ 35 ] Higher B7-H3 expression on tumors in human immunodeficiency virus (HIV)-infected lung cancer patients as compared with uninfected patients may provide clues for the treatment of HIV-infected lung cancer patients.…”