Abnormal activation of NF-B and MAPK signaling pathways affect osimertinib resistance and influence the recruitment of myeloid-derived suppressor cells to shape the immunosuppressive tumor immune microenvironment

Background: Osimertinib is the first-line treatment for patients with epidermal growth factor receptor (EGFR) mutations, but the treatment options after drug resistance are limited. Previous studies have suggested that EGFR is in an immunosuppressive tumor immune microenvironment (TIME). However, the evolution of TIME after osimertinib resistance and whether this resistance can be overcome by targeting TIME needs to be further investigated.Methods: The remodeling process and mechanism of TIME during the treatment with osimertinib were studied.Results: The proportion of EGFR(L858R+T790M) mutant tumor immune infiltrating cells was extremely low. Osimertinib treatment transiently triggered inflammatory cells, but several immunosuppressive cells infiltrated after drug resistance and formed a myeloid-derived suppressor cell (MDSC)-enriched TIME. The programmed cell death protein-1 monoclonal antibody was not able to reverse the MDSC-enriched TIME. Further analysis revealed that the activation of nuclear factor-kappa B (NF-?B) and mitogen-activated protein kinase (MAPK) pathways recruited a large number of MDSCs via cytokines. Finally, MDSC secreted high levels of interleukin-10 and arginase-1 and created an immunosuppressive TIME.Conclusions: Thus, our findings lay the foundation for the evolution of TIME in osimertinib treatment, establish the mechanism of immunosuppressive TIME after osimertinib resistance, and propose potential solutions.