Adenocarcinoma of the uterine cervix shows impaired recruitment of cDC1 and CD8+ T cells and elevated β-Catenin activation compared to squamous cell carcinoma.

Purpose: Adenocarcinoma (AC) of the uterine cervix is the second most common type of cervical cancer after squamous cell carcinoma (SCC). Although both subtypes are treated similarly, patients with AC have a worse prognosis. In this study, immunologic features of the tumor microenvironment in these two subsets were pursued with potential therapeutic implications. Experimental Design: The immune microenvironment of primary tumors (PT) and non-metastatic tumor-draining lymph nodes (TDLN) was compared between patients with cervical AC (n = 16) and SCC (n = 20) by polychromatic flow cytometry and by transcriptional profiling of the PT (n = 299) using publicly available data from The Cancer Genome Atlas (TCGA). Results: Flowcytometric analyses revealed intact T-cell differentiation in TDLN but hampered effector T-cell trafficking to the PT in AC, as compared to SCC. TCGA analysis demonstrated higher expression of chemokines involved in effector T-cell homing (CXCL9/10/11) in SCC PT as compared to AC PT, which was highly correlated to a transcriptional signature for type 1 conventional dendritic cells (cDC1). This was consistent with elevated frequencies of CD141+/BDCA3+ cDC1 in PT SCC samples relative to AC and correspondingly elevated levels of CXCL9 and CXCL10 in 24h ex-vivo cultures. Hampered cDC1 recruitment in AC was in turn related to lower transcript levels of cDC1-recruiting chemokines and an elevated β-catenin activation score, and was associated with poor overall survival. Conclusions: Our data have identified an opportunity for the investigation of potentially novel therapeutic interventions in AC of the cervix, i.e. β-catenin inhibition and cDC1 mobilization.