<i>MiR-155</i>-targeted IcosL controls tumor rejection.

Abstract

Elevated levels of <i>miR-155</i> in solid and liquid malignancies correlate with aggressiveness of the disease. In this manuscript, we show that <i>miR-155</i> targets transcripts encoding IcosL, the ligand for Inducible T-cell costimulator (Icos), thus impairing the ability of T cells to recognize and eliminate malignant cells. We specifically found that overexpression of <i>miR-155</i> in B cells of Eµ-<i>miR-155</i> mice causes loss of IcosL expression as they progress toward malignancy. Similarly, in mice where <i>miR-155</i> expression is controlled by a Cre-Tet-OFF system, <i>miR-155</i> induction led to malignant infiltrates lacking <i>IcosL</i> expression. Conversely, turning <i>miR-155</i> OFF led to tumor regression and emergence of infiltrates composed of IcosL-positive B cells and Icos-positive T cells forming immunological synapses. Therefore, we next engineered malignant cells to express IcosL, in order to determine whether <i>IcosL</i> expression would increase tumor infiltration by cytotoxic T cells and reduce tumor progression. Indeed, overexpressing an <i>IcosL</i>-encoding cDNA in MC38 murine colon cancer cells before injection into syngeneic C57BL6 mice reduced tumor size and increased intratumor CD8+ T cell infiltration, that formed synapses with IcosL-expressing MC38 cells. Our results underscore the fact that by targeting <i>IcosL</i> transcripts, <i>miR-155</i> impairs the infiltration of tumors by cytotoxic T cells, as well as the importance of IcosL on enhancing the immune response against malignant cells. These findings should lead to the development of more effective anticancer treatments based on maintaining, increasing, or restoring IcosL expression by malignant cells, along with impairing <i>miR-155</i> activity.