IFNg-mediated reprogramming of antigen presenting cell (IMRAPC) behavior in keratinocytes is perturbed in skin cancer

Summary: Abstract Body: Keratinocytes (KCs) provide a barrier yet its role for tumor immunosurveillance is not well known. IFNγRa-KO mice exhibit increased tumor formation upon MCA induction. Its ligand IFNγ induces MHC Class II in KCs that is restricted to professional antigen presenting cells (APCs). The findings suggest an IFNg-mediated reprogramming of antigen presenting cell (IMRAPC) behavior in KCs for tumor immunosurveillance that is poorly understood. We determined the transcriptomes of normal KCs (N/TERT) and A431 epidermoid carcinoma KCs upon IFNγ and evaluated its impact in Organotypic Epithelial Raft Cultures (OERCs) with Transepithelial Electrical Resistance (TEER) assays. RNA-seq identified IFNγ induction of CXCL10 and -11 chemoattractant expressions which coincided with MHC Class II (HLA-DRA and -B1) resulting in stable cell surface MHC Class II localization in both cell types (vs untreated) but decreased in A431 (p<0.001). However, T cell costimulatory molecule CD58 was compromised in A431 vs N/TERT (p<0.001) revealing aberrant IMRAPC reprogramming in A431 cells. IFNγ treatment in N/TERT OERC resulted in KRT14/K1 epidermal thickening and reduced TEER vs untreated N/TERT (p<0.05) in contrast to less stratified and undifferentiated epidermis (KRT14 only) and reduction in TEER in A431 OERCs vs untreated A431 (p<0.05). Suprabasal expression of CD58 was also dampened in A431. The findings identify IMRAPC remodelling of KCs that compromises barrier function and is aberrant in A431. We sought to further determine the clinical relevance of IMRAPC in skin cancer. We found HLA-DR+CD45- expression in moderate to severe human KRT+ cSCC tumor borders. Our findings identify IMRAPC remodelling in KCs that is compromised in epidermoid carcinoma KCs and tumors and provide opportunities to develop new skin cancer treatments. Niharika Srivastava¹, Angelica Guardia¹, Mohammed Barmal², Indra Adrianto², Jesse Veenstra¹, Cristina de Guzman Strong^{1, 3} 1. Dermatology, Henry Ford Health System, Detroit, MI, United States. 2. Public Health Sciences, Henry Ford Health System, Detroit, MI, United States. 3. Medicine, Michigan State University, East Lansing, MI, United States. Cell Communication Networks and Stromal Biology