Impact of EGFR-TKIs combined with PD-L1 antibody on the lung tissue of EGFR-driven tumor-bearing mice

Abstract Objectives EGFR-targeted tyrosine kinase inhibitors (TKIs) have been the standard treatment for non-small cell lung cancer patients with EGFR mutations. However, most patients eventually develop resistance. With the development of immune checkpoint inhibitors targeting the programmed cell death receptor/ligand 1 (PD-1/PD-L1), there is a growing interest in developing combination strategies. However, there are concerns that the combination of a PD-(L)1 inhibitor and EGFR-TKI may be associated with an increased risk of pneumonitis. Therefore, we utilized an established EGFR-driven tumor-bearing mouse model to investigate whether the combination would induce pneumonitis in mouse lung tissue. Materials and Methods Mice were treated with monotherapy or combined therapy of PD-L1 antibody and EGFR-TKIs including first-generation gefitinib and third-generation osimertinib. Bronchoalveolar lavage fluids (BALFs) and lung tissues were collected for analysis at the end of treatment. Results and Conclusion The osimertinib and anti-PD-L1 combined treatment group had the highest inflammation scores in pathologic grades of H&E staining of lung tissue and had the highest percentages of myeloperoxidase positive cells. However, combining gefitinib and anti-PD-L1 treatment appeared to not increase the level of pneumonitis in mice. Total cell counts, neutrophil counts and total protein concentration in BALFs were also significantly increased in the osimertinib and anti-PD-L1 combined treatment group. We next evaluated proinflammatory factors in BALFs. The levels of IFN-γ, IL-2, IL-5, TNF-α and IL-12p70 were increased in osimertinib and anti-PD-L1 combined treatment group. Comparison of different sequences of drug administration demonstrated that mice treated with osimertinib followed by PD-L1 antibody did not show evident lung inflammation. Our findings indicate that osimertinib, rather than gefitinib combined with anti-PD-L1 treatment could lead to lung injury in an EGFR mutated tumor-bearing mouse model. The sequence and timing of combining EGFR-TKI and PD-L1 antibody may influence the severity of pneumonitis.