EGFR-TKI resistance promotes immune escape in lung cancer via increased PD-L1 expression

Background The ATLANTIC trial reported that higher PD-L1 expression in tumors was involved in a higher objective response in patients with EGFR+/ALK+ non-small cell lung cancer (NSCLC), indicating the possibility of anti-PD-1/PD-L1 therapy as a third-line (or later) treatment for advanced NSCLC. Therefore, the determination of status and regulatory mechanisms of PD-L1 in EGFR mutant NSCLC before and after acquired EGFR-TKIs resistance are meaningful. Methods The correlation among PD-L1, c-MET, and HGF was analyzed based on TCGA datasheets and paired NSCLC specimens before and after acquired EGFR-TKI resistance. EGFR-TKI resistant NSCLC cells with three well-known mechanisms, c-MET amplification, hepatocyte growth factor (HGF), and EGFR-T790M, were investigated to determinate PD-L1 expression status and immune escape ability. PD-L1-deleted EGFR-TKIs sensitive and resistant cells were used to evaluate the immune escape ability of tumors in mice xenograft models. Results Positive correlations were found among PD-L1, c-MET, and HGF, based on TCGA datasheets and paired NSCLC specimens. Moreover, the above three resistant mechanisms increased PD-L1 expression and attenuated activation and cytotoxicity of lymphocytes in vitro and in vivo, and downregulation of PD-L1 partially restored the cytotoxicity of lymphocytes. Both MAPK and PI3K pathways were involved in the three types of resistance mechanism-induced PD-L1 overexpression, whereas the NF-kappa B pathway was only involved in T790M-induced PD-L1 expression. Conclusions HGF, MET-amplification, and EGFR-T790M upregulate PD-L1 expression in NSCLC and promote the immune escape of tumor cells through different mechanisms.

Modification of immune response to xenogeneic embryonic proteins by adjuvants of microbial origin

<p>Blood serum of BALB/c mice immunized with chicken embryonic proteins (CEP) in combination with adjuvants<br />of microbial origin has been investigated by methods of enzyme immunoassay and immunoblotting. The analysis<br />of accumulation of antibodies to CE P and the study of antibody-dependent cytotoxicity of lymphocytes against the<br />tumor cells of the model suggest that the use of adjuvants of microbial origin, such as protein-containing metabolites<br />of culture fluid (18.5 and 70 kDa) and lipid fraction of В. subtilis B-7025 cells; S. aureus cell-wall peptidoglycan,<br />contributes to credible strengthening of immune response to fetal antigens. The results of the study are the basis<br />for creating xenogenic cancer vaccine.</p>