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

Abstract 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.