Colony-Stimulating Factor-1 Receptor Inhibitor Augments Osimertinib-Induced Antitumor Immunity via Suppression of Macrophages in Lung Cancer Harboring <i>EGFR</i> Mutation

Persister cancer cells, which reversibly adapt to survive EGFR-tyrosine kinase inhibitor (TKI) 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. 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 the genetically engineered mouse model were transplanted subcutaneously into wild-type C57BL/6J mice. Persistent tissues under osimertinib treatment were analyzed using digital spatial transcriptional profiling, IHC staining, and flow cytometry. The antitumor 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 antitumor effect of osimertinib. Digital spatial transcriptional profiling revealed upregulated expression of M2 macrophage-related genes in the TME of persister cancer cells. Consistently, IHC and flow cytometry confirmed an increased number of CD206+ macrophages in the TME. Combining osimertinib with the colony-stimulating factor-1 receptor inhibitor pexidartinib reduced CD206+ macrophages and enhanced the efficacy of osimertinib. Elevated Granzyme B or CD107 expression on CD8+ cells in the TME suggests that macrophages negatively affect osimertinib-induced antitumor immunity. M2-like macrophages may contribute to the immune tolerance of persister cancer cells against EGFR-TKI-induced tumor immunity. A clinical trial evaluating combined osimertinib and colony-stimulating factor-1 receptor inhibitor therapy is warranted for EGFR-mutated lung cancer.