The role of BATF2 deficiency in immune microenvironment rearrangement in cervical cancer - New biomarker benefiting from combination of radiotherapy and immunotherapy

Abstract

Despite the significant progress in immunotherapy for certain cancers, including cervical cancer, most patients remain unresponsive or derive limited benefits from combined radiotherapy and chemotherapy. The factors underlying treatment resistance are unknown and there are few reliable predictive biomarkers. BATF2 is a member of the basic leucine zipper transcription factor family and is involved in immune response and immune cell development. However, the role of BATF2 in the immune microenvironment of patients with cervical cancer after radiotherapy remains unclear. In this study, immunohistochemistry and multicolour immunofluorescence analyses of patient tumor samples were used to assess BATF2 expression. We found that cervical cancer patients with high BATF2 expression had higher infiltration levels of CD4⁺ T cells, CD8⁺ T cells, and macrophages within the tumor than those with low expression levels. Furthermore, BATF2 expression was positively correlated with the prognosis of patients after concurrent chemoradiotherapy. A wild-type mouse model with BATF2-knockdown U14 cell-derived subcutaneous tumors and a Batf2^-/- mouse model with wild-type U14 cell-derived subcutaneous tumors were used to assess CD8⁺ T cell infiltration and function. As expected, the knockdown of BATF2 in the U14 cell line substantially promoted tumor growth, which was mediated by a reduction in CD8⁺ T cell infiltration and antitumor function in vivo. Additionally, the Batf2^-/- mouse model demonstrated that host BATF2 is also involved in controlling tumor growth. Furthermore, the combination of radiotherapy and anti-PD-1 therapy showed synergistic antitumour effects. These findings collectively suggest that BATF2 may serve as a potent positive regulator of the tumor immune microenvironment of cervical cancer after radiotherapy, and has the potential to be a prognostic biomarker to guide the application of a combination of radiotherapy and immunotherapy.

Keywords: BATF2; Cervical cancer; Concurrent chemoradiotherapy; Immune microenvironment.