NKG2D enhances chemosensitivity to cisplatin in patients with extensive small cell lung cancer by up-regulating NF-κβ2

Background: Extensive small cell lung cancer (SCLC) still does not have a method to significantly improve the efficacy of chemotherapy, often resulting in chemotherapy failure due to rapid drug resistance. Recently, the role of immunization in the treatment of cancer has been paid more and more attention, so the role of immune-related genes in chemotherapy needs further research. In this study, the effects of NKG2D on chemotherapy to etoposide combined with cisplatin were studied, and the mechanism was researched. Methods: 152 patients with extensive SCLC diagnosed by pathology were included in the study. Tumor tissues were subjected to NKG2D immunohistochemistry and quantified. Then the patient's NKG2D expression level was correlated analyzed with etoposide combined with cisplatin chemotherapy asymptomatic survival time (PFS) and overall survival time (OS). Through the whole-genome transcriptome sequencing, the possible pathways of NKG2D were found, and high-expression and interfering NCI-H446 cell lines were constructed for pathway validation. Results: The expression level of NKG2D in 152 tumor tissues showed a normal distribution. Correlation analysis showed that it had a significant positive correlation with PFS (R2=0.283, P = 0.006) and OS (R2=0.235, P = 0.022). In addition, we found that the top 20 patients with the highest NKG2D expression had a longer median PFS than the lowest 20 patients for 3.5 months (9.2 months vs. 5.7 months, P < 0.05). It is worth noting that the median OS is more obviously extended (23.3 months v.s. 10.4 months, P < 0.01). Transcriptome detection of tumor tissues in patients with high expression of NKG2D revealed that NKG2D up-regulated NKG2DLs, apoptotic genes, DNA damage repair genes and nuclear factor (NF) family genes. In vitro, IC50 value to cisplatin of NKG2D over-expressed NCI-H446 cell was significantly lower than control. Then, we interfered with NF-κβ2 and found that it inhibited the chemosensitivity of NKG2D over-expression cell lines to cisplatin. Conclusions: NKG2D is a predictive and prognostic factor for chemotherapy in patients with extensive small cell lung cancer, possibly be achieved by upregulating NF-κβ2. Legal entity responsible for the study: Medical Science and Technology Program of Henan Province. Funding: Has not received any funding. Disclosure: All authors have declared no conflicts of interest.