LIN28/ <i>let-7</i> /PD-L1 Pathway as a Target for Cancer Immunotherapy

Abstract

The immunocheckpoint protein PD-1/PD-L1 is considered a promising target for cancer immunotherapeutics. However, the objective response rate using antibodies that block the interaction between PD-1 and PD-L1 was less than 40%, and the mechanism underlying regulation of PD-1/PD-L1 expression is poorly understood. In this study, we identified the miRNA <i>let-7</i> that posttranscriptionally suppresses PD-L1 expression. LIN28, an RNA binding protein upregulated in most cancer cells, inhibits the biogenesis of <i>let-7</i>, thus promoting PD-L1 expression. Therefore, inhibition of LIN28 may be a strategy to prevent immune evasion of cancer cells. We found that treatment with a LIN28 inhibitor, the small compound C1632, increases <i>let-7</i> and suppresses PD-L1 expression, leading to reactivation of antitumor immunity <i>in vitro</i> and <i>in vivo</i> In addition, C1632 also displayed the capacity to inhibit cancer cell proliferation and tumor growth in mice. Altogether, these findings identified LIN28/<i>let-7</i> as a target for PD-L1-mediated immunotherapeutics and reveal the potential of C1632 and its derivatives as promising oncotherapeutic agents.