Inflammatory pathways confer resistance to chemoradiotherapy in anal squamous cell carcinoma

Acantholytic squamous cell carcinoma (ASCC) is associated with immunosuppression and infection with human papillomavirus (HPV). Response to standard chemoradiotherapy (CRT) varies considerably. A comprehensive molecular characterization of CRT resistance is lacking, and little is known about the interplay between tumor immune contexture, host immunity, and immunosuppressive and/or immune activating effects of CRT. Patients with histologically confirmed, localized ASCC, treated between 1998 and 2019 at three different sites (Frankfurt, Berlin, Tübingen) of the German Cancer Consortium (DKTK) were included. All patients received 5-FU/MMC-based CRT. Patient cohorts for molecular analysis were defined based on availability and quality of samples, including baseline formalin fixed paraffin embedded biopsies for immunohistochemistry (n=130), baseline RNA sequencing (n=98), peripheral blood immune profiling by sequential multiparametric flow cytometry (n=47), and serum cytokine multiplex assays measurement (n=35). Tumor response, freedom from locoregional failure (FFLF), and freedom from distant metastasis (FFDM) were correlated with clinicopathologic and molecular findings.