MiR-155-targeted IcosL controls tumor rejection

• 成果类型: Article
• 署名作者: Tili, Esmerina; Otsu, Hajime; Commisso, Teresa L.; Palamarchuk, Alexey; Balatti, Veronica; Michaille, Jean-Jacques; Nuovo, Gerard James; Croce, Carlo M.
• 署名单位: University System of Ohio; Ohio State University; University System of Ohio; Ohio State University; James Cancer Hospital & Solove Research Institute
• 刊物名称: PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
• ISSN/ISSBN: 0027-10000
• DOI: 10.1073/pnas.2408649121
• 发表日期: 2024-07-16
• 关键词: t-cell-activation; b-cells; inducible costimulator; microrna-155; expression; receptor; mir-155; b7h; stimulation; prognosis

摘要

Elevated levels of miR-155- 155 in solid and liquid malignancies correlate with aggressiveness of the disease. In this manuscript, we show that miR-155- 155 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 over- expression of miR-155- 155 in B cells of E mu- miR- 155 mice causes loss of IcosL expression as they progress toward malignancy. Similarly, in mice where miR-155- 155 expression is controlled by a Cre-Tet-OFF- Tet- OFF system, miR-155- 155 induction led to malignant infiltrates lacking IcosL expression. Conversely, turning miR-155- 155 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 IcosL expression would increase tumor infiltration by cytotoxic T cells and reduce tumor progression. Indeed, overexpressing an IcosL-- 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 IcosL transcripts, miR-155- 155 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 miR-155- 155 activity.