Hippo pathway as another oncogenic mediator to promote immune evasion by PD-L1 signaling

The programmed cell death protein (PD)-1 and programed death ligand 1 (PD-L1) based immunotherapeutic agent is a cornerstone for the treatment of cancer. The expression of PD-L1 was developed as a biomarker to predict the efficacy of anti-PD1/PD-L1 pathway based immune check point inhibitor. In addition, increased PD-L1 in tumor and tumor microenvironment could be considered as representative biomarkers for immune suppressive microenvironment. The expression of PD-L1 is known to be increased by innate immune resistance as well as acquired immune resistance (1). In acquired immune resistance, the expression of PD-L1 secondarily increased by interferon (IFN) gamma secreted by immune cells including cytotoxic T cells in inflamed tumor, but in case of innate immune resistance the expression of PD-L1 increased directly by oncogenic signaling pathway which might be not related to inflamed tumor microenvironment (2). The expression of PD-L1 may not predict the effect of the anti-PD1 pathway based immune check point inhibitor in case of PD-L1 of tumors directly elevated by the oncogenic signal pathway, however the increased PD-L1 itself is likely to induce immune resistance in tumor. The regulation of PD-L1 by oncogenic signaling pathway already has been known in various type of cancer including non-small cell lung cancer (3-7). Activation of common oncogenic signaling pathways such as EGFR, EML4-ALK, JAK/STAT, RAS/ERK, or PI3K/AKT/MTOR has been shown to affect tumoral PD-L1 expression (3-6). The regulation of PD-L1 expression by oncogenic signaling pathway can act either directly on specific target sequence of PD-L1 or indirectly mediated by the activation of transcription factors. Molecules as IRF-1, STAT3, STAT1, c-Jun, HIFs, or NF-κB as a transcription factor can migrate to the nucleus, bind to specific sequence of promoter of PD-L1 to induce its expression (7)