Cervical cancer cells suppress effector functions of cytotoxic T cells through the adenosinergic pathway

Abstract

BackgroundThe expression of CD73 in tumor cells plays a significant role in the production of adenosine (Ado) that suppresses antitumor effector cells. MethodsIn this study we analyzed the capability of HPV-positive (HPV+) cervical cancer (CeCa) cell lines CaSki, SiHa, HeLa, and RoVa; and HPV-negative (HPV−) cell lines C33A and ViBo to produce Ado and inhibit effector functions of CD8+ T cells. ResultsHPV+ CeCa cells expressed significantly higher levels of CD73 in the membrane (p<0.01) than HPV− CeCa cells and this expression was associated with the production of larger amounts of Ado (>400μM) compared to HPV-CeCa cells (<200μM) in the presence of AMP, as well asa stronger inhibition of (>50%) proliferation, activation, and cytotoxic activity of CD8+ T cells via interaction with A2A adenosine receptor. We also provide evidence that silenced E6/E7 expression in CeCa cells, strongly reduced its CD73 expression level and its capability to generate Ado. ConclusionThis results suggest that HPV infection, which is associated with more than 99% of CeCa cases, may present an increased constitutive expression of CD73 in cervical neoplasia to contribute to the suppression of the immune response mediated by the production of large amounts of Ado.