Abstract / Summary
Abstract Despite of the dramatic antitumor effects of small-molecule tyrosine kinase inhibitors (TKIs), patients with oncogene-driven non-small cell lung cancer (driver-positive NSCLC) inevitably experience recurrence because of the existence of intrinsic drug-resistant subpopulation called drug-tolerant persisters (DTPs). We here examined whether innate immunity could eliminate DTPs in driver-positive NSCLC. In specific TKI-exposed driver-positive NSCLC cells, transcripts of galectin-9 (Gal-9), one of immune checkpoint molecules, were drastically upregulated via activation of interferon regulatory factor 1 in nucleus. Cytotoxicity assay by co-incubating cancer cells and natural killer (NK) leukemia (NKL) cells revealed that NK cell-mediated cytotoxicity was weakened by Gal-9 expression in cancer cells. Notably, while CRISPR/Cas9-mediated Gal-9-knockout (KO) cells were completely depleted by TKI exposure plus NKL mediated-cytotoxicity, scramble guide RNA-transfected cells reproliferated, which suggested that NKL-mediated cytotoxicity reinforced by Gal-9 depletion could eliminate DTPs. Then, athymic nude mice inoculated with driver-positive NSCLC cells were treated with TKI. The regrowth of Gal-9-KO driver-positive NSCLC xenografts and allografts were significantly suppressed by NK cell-mediated cytotoxicity. Furthermore, Gal-9 expression was associated with worse progression free survival in human epidermal growth factor receptor mutation-positive NSCLC. These findings identified Gal-9 as an inducer of immune-evasion and elucidated its therapeutic targeting to eliminate DTPs.