ACLP Activates Cancer-Associated Fibroblasts and Inhibits CD8+ T-Cell Infiltration in Oral Squamous Cell Carcinoma

SIMPLE SUMMARY: Cancer-associated fibroblasts (CAFs) are a major component of the stroma in oral squamous cell carcinoma (OSCC) and are considered important therapeutic targets. In this study, we demonstrated that aortic carboxypeptidase-like protein (ACLP) is highly expressed in CAFs of OSCC, thereby activating them. Cancer cells induce ACLP expression in CAFs through the TGF-β1 signaling pathway, and CAF-derived ACLP enhances the migration and infiltration of cancer cells. Furthermore, ACLP co-expresses with collagen and shows an inverse correlation with tumor infiltration of CD8+ T lymphocytes. Our data suggest that targeting ACLP could be a potential approach for stromal-targeted therapy and a novel target for cancer immunotherapy. ABSTRACT: We previously showed that upregulation of adipocyte enhancer-binding protein 1 (AEBP1) in vascular endothelial cells promotes tumor angiogenesis. In the present study, we aimed to clarify the role of stromal AEBP1/ACLP expression in oral squamous cell carcinoma (OSCC). Immunohistochemical analysis showed that ACLP is abundantly expressed in cancer-associated fibroblasts (CAFs) in primary OSCC tissues and that upregulated expression of ACLP is associated with disease progression. Analysis using CAFs obtained from surgically resected OSCCs showed that the expression of AEBP1/ACLP in CAFs is upregulated by co-culture with OSCC cells or treatment with TGF-β1, suggesting cancer-cell-derived TGF-β1 induces AEBP1/ACLP in CAFs. Collagen gel contraction assays showed that ACLP contributes to the activation of CAFs. In addition, CAF-derived ACLP promotes migration, invasion, and in vivo tumor formation by OSCC cells. Notably, tumor stromal ACLP expression correlated positively with collagen expression and correlated inversely with CD8+ T cell infiltration into primary OSCC tumors. Boyden chamber assays suggested that ACLP in CAFs may attenuate CD8+ T cell migration. Our results suggest that stromal ACLP contributes to the development of OSCCs, and that ACLP is a potential therapeutic target.