Colony-stimulating factor-1 receptor inhibitor augments osimertinib-induced anti-tumor immunity via suppression of macrophages in lung cancer harboring EGFR mutation.

Abstract

Persister cancer cells, which reversibly adapt to survive epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitors (TKIs) treatment, contribute to the incurability of EGFR-mutant lung cancer. We previously reported that gefitinib induces CD8⁺ T cell-related tumor immunity in a genetically engineered mouse model (GEMM). This study investigates the tolerance of persister cancer cells to EGFR-TKI-induced tumor immunity in this model. Egfr-mutated lung cancer cells (C57BL/6/EgfrdelE748-A752) from GEMM were transplanted subcutaneously into wild-type C57BL/6J mice. Persistent tissues under osimertinib treatment were analyzed using digital spatial transcriptional profiling (DSP), immunohistochemical staining (IHC), and flow cytometry (FCM). The anti-tumor effect of osimertinib peaked at 14 days, leaving a small population of persister cancer cells. The number of PD-1⁺ CD8⁺ cells increased in the tumor microenvironment (TME), and CD8⁺ cell depletion attenuated the anti-tumor effect of osimertinib. DSP revealed upregulated expression of M2 macrophage-related genes in the TME of persister cancer cells. Consistently, IHC and FCM confirmed an increased number of CD206⁺ macrophages in the TME. Combining osimertinib with the colony-stimulating factor-1 receptor (CSF1R) inhibitor pexidartinib reduced CD206⁺ macrophages and enhanced the efficacy of osimertinib. Elevated granzyme or CD107 expression on CD8⁺ cells in the TME suggests that macrophages negatively affect osimertinib-induced anti-tumor immunity. M2-like macrophages may contribute to immune tolerance of persister cancer cells against EGFR-TKI-induced tumor immunity. A clinical trial evaluating combined osimertinib and CSF1R inhibitor therapy is warranted for Egfr-mutated lung cancer.