The tRF-3024b hijacks miR-192-5p to increase BCL-2-mediated resistance to cytotoxic T lymphocytes in Esophageal Squamous Cell Carcinoma

Abstract

The limited efficacy of immune checkpoint inhibitors (ICIs) in the treatment of advanced Esophageal Squamous Cell Carcinoma (ESCC) poses a challenge. Recent evidence suggests that tumor cells' insensitivity to cytotoxic T lymphocytes (CTLs) contributes to drug resistance against ICIs. Here, a particular tRNA-derived fragment called tRF-3024b has been identified as playing a significant role in tumor cell resistance to CTLs. Through tRF sequencing (tRF-seq), we observed a high expression of tRF-3024b in ESCC cells that survived co-culture with CTLs. Further in vitro studies demonstrated that tRF-3024b reduced the apoptosis of tumor cells when co-cultured with CTLs. The mechanism behind this resistance involves tRF-3024b promoting the expression of B-cell lymphoma-2 (BCL-2) by sequestering miR-192-5p, a microRNA that would normally inhibit BCL-2 expression. This means that tRF-3024b indirectly enhances the protective effects of BCL-2, reducing apoptosis in tumor cells. Rescue assays confirmed that the suppressive function of tRF-3024b relies on BCL-2. In summary, the tRF-3024b/miR-192-5p/BCL-2 axis sheds light on the crucial role of tRF-3024b in regulating BCL-2 expression. These findings offer valuable insights into strategies to enhance the response of ESCC to CTLs and improve the effectiveness of immunotherapy approaches in treating ESCC.