西野 宏

Abstract Antibody-dependent cellular cytotoxicity (ADCC) is a key player in the antitumor immunity elicited through molecular targeted therapy of oncogenic receptors using monoclonal antibodies (mAb). Oncolytic viruses represent an alternative therapeutic means that selectively replicate in and destroy tumor cells, as well as induce specific antitumor immune responses. This study investigates whether oncolytic virus therapy using G47Δ, a third-generation oncolytic herpes virus with enhanced induction of antitumor immunity, can augment the efficacy of molecular targeted therapy with ADCC using the anti–epidermal growth factor receptor (EGFR) mAb cetuximab. Due to the species specificity of cetuximab, we developed a human EGFR-expressing immunocompetent murine tumor model specific to the ADCC activity of cetuximab. Intratumoral G47Δ administration combined with systemic cetuximab treatment was significantly more effective in suppressing tumor growth than G47Δ monotherapy. This phenomenon was dependent upon the activation of both innate and adaptive immune cells, as antitumor responses were abrogated upon natural killer cell and CD8+ T-cell depletion. Further studies investigating the draining lymph node dendritic cells (DC) indicate that the destruction of cetuximab-coated tumor cells by G47Δ promotes uptake of tumor cells by DCs, enhances the priming of immune responses, and subsequently stimulates tumor-specific CD8+ T cells. These results suggest that the combination of G47Δ therapy and molecular targeted therapies with ADCC activity may represent a useful therapeutic strategy for enhancing antitumor immune responses, even after the emergence of acquired resistance.

BACKGROUND/AIM: The Hippo signaling pathway comprises mammalian sterile 20-like kinase 1/2, large tumor suppressor 1/2, and Yes-associated protein 1 (YAP1). This study investigated phosphorylated YAP (pYAP, Ser 127) protein expression in oral squamous cell carcinoma (OSCC). PATIENTS AND METHODS: Tissues from patients with oral epithelial dysplasia (OED, n=7), carcinoma in situ (CIS, n=14), and OSCC (n=109) were analyzed. RESULTS: Cytoplasmic expression of pYAP was low in OED, CIS, and OSCC tissues. The expression of pYAP was correlated with differentiation, and the expression of low levels of YAP was significantly more common in well-differentiated to moderately differentiated OSCC than in poorly differentiated OSCC. High pYAP expression correlates with characteristics of epithelial-to-mesenchymal transition (EMT), e.g., loss of E-cadherin and increased expression of vimentin and laminin 5 (p<0.0001). Additionally, the protein arginine methyltransferase 1, a positive modulatory factor of YAP activity, was found to be correlated with elevated levels of pYAP expression (p<0.0007). CONCLUSION: The presence of elevated pYAP expression may serve as a prognostic indicator of an aggressive OSCC with EMT during the invasive stage.