The concurrent silencing of Tim-3 and STAT-3 promotes tumor regression both in vitro and in ovo.

Abstract

Background: Due to the intricate nature of the tumor microenvironment and the impairment of the anti-tumor responses of the immune system, finding a novel approach in the field of immunology-based therapy might influence the prognosis and survival of patients suffering from cancer. T-cell immunoglobulin and mucin-domain containing-3 (Tim-3) is a regulatory element of immune surveillance that exerts a pivotal function in the microenvironment of tumors. Although the precise functions of the Tim-3 remain incompletely understood, it has been established that it not only contributes to T cell exhaustion but also participates in the STAT-3/NF-κB (signal transducer and activator of transcription 3 / nuclear factor-κB) pathway, which plays a major role in the progression of tumors.

Methods: In this research, we assessed the efficacy of co-blocking the Tim-3 and STAT-3 factors in inhibiting cancer cell growth. Therefore, we suppressed the expression of these factors in murine-derived malignant cell lines (4T1 and CT26), using siRNA (small interfering RNA) molecules encapsulated in chitosan lactate-based nano carriers we previously developed.

Results: Transfecting the siRNAs into cancer cells with nanocarriers significantly downregulated the expression of Tim-3 and STAT-3 in both 4T1 and CT26 cells. Downregulation of Tim-3 and STAT-3 was correlated with diminished viability, proliferation, angiogenesis, and metastatic characteristics of cancerous cells, in vitro. Furthermore, co-silencing of Tim-3 and STAT-3 led to tumor regression, in ovo.

Conclusion: These results revealed that the concurrent silencing of Tim-3 and STAT-3 can significantly suppresses the tumor growth by reducing cell proliferation, angiogenesis and metastasis in vitro and in ovo. However, future investigations-particularly in vivo models-are necessary to validate the current strategy as a potential anti-tumor therapeutic approach.