Abstract 231: Targeting CXCL17 (C-X-C Motif Chemokine Ligand 17) inhibits cutaneous squamous cell carcinoma via modulating angiogenesis

Abstract

Abstract Cutaneous squamous cell cancer (cSCC) is one of the most rapidly increasing cancers in the USA, striking 200,000 Americans annually, and is associated with significant morbidity & mortality. Exposure to Solar UVB (ultraviolet B) radiation is the primary etiologic factor for skin cancer. Sunscreens provide limited protection against UVB-induced skin cancer, and there is no effective adjuvant therapy for aggressive cSCC. Therefore, new mechanism-based approaches are needed for both prevention of cSCC and as adjuvant treatment for patients at high risk for recurrence and metastasis. Moreover, excision of cSCC of the Head & Neck results in significant facial disfigurement, and thus, chemoprevention for patients with condemned skin is critical. Chemokine (C-X-C motif) ligand 17 (CXCL17) is the latest chemokine family member, and recent studies have identified both a causative and protective role of CXCL17 in tumorigenesis. The role of CXCL17 in the development and progression of cSCC is not yet elucidated. In our ongoing studies, CXCL17 protein expression was significantly overexpressed in cSCC cell lines (SCC12A, SCC118, SCC7, SCC59) compared to normal human epidermal keratinocytes. Deletion of CXCL17 significantly inhibited cSCC cell proliferation, migration, and motility, suggesting an essential role in tumor growth, invasion, and metastasis. Tumor-specific overexpression of CXCL17 was detected in human cSCC that further bolsters our in vitro findings, indicating a causative role for CXCL17 in skin tumorigenesis. Further, deletion of CXCL17 in cSCC cell lines was associated with marked downregulation of the AKT/mTOR/STAT3 cell signaling pathways. To translate our in vivo data in an in vivo animal model, the effect of CXCL17 deletion on cSCC tumor cell xenograft growth was evaluated. Deletion of CXCL17 in both non-metastatic and metastatic cSCC cells significantly decreased tumor growth. Moreover, the reduction in tumor growth was associated with a significant downregulation in tumor angiogenesis measured using IHC for CD31. Finally, using a retrospective chart review for patients at Louisiana State University Health Sciences Center Shreveport (LSUHSC-S) and Overton Brooks Veterans Affairs Medical Center, we investigated the correlation of CXCL17 staining in human cSCC tumor samples and clinicopathological factors associated with metastatic cSCC. Among 44 subjects included in the analysis, the Histo-score of cytoplasmic CXCL17 expression was significantly higher in the metastatic cSCC group compared to non-metastatic tumor samples. Interestingly, the CXCL17 staining score correlated with the perineural invasion, suggesting CXCL17 as a biomarker of aggressiveness. Our studies have established a causative role for CXCL17 in cSCC and a novel target in the treatment of cSCC Citation Format: Alok R. Khandelwal, Rema Anisha Kandula, Md Maksudul Alam, Janmaris Marin Fermin, Tara Moore-Medlin, John DiGiovanni, Cherie-Ann O. Nathan. Targeting CXCL17 (C-X-C Motif Chemokine Ligand 17) inhibits cutaneous squamous cell carcinoma via modulating angiogenesis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 231.