Chronic inflammation is a well-known driver of lung cancer and influences the efficacy of standard therapies, including immune checkpoint blockade (ICB) in KRAS-mutant tumors and osimertinib response in EGFR-driven tumors. Previously, we demonstrated that reduced expression of the potent anti-inflammatory protein A20 correlates with improved ICB response in KRAS-mutant lung tumors. Here, we investigated whether targeting A20 could similarly enhance ICB susceptibility in EGFR-driven lung tumors.

We generated a genetically modified mouse model to study the initiation and progression of EGFR-L858R mutant lung tumors, focusing on the impact of A20 expression on the tumor microenvironment.

Our study reveals a distinct anti-inflammatory role of A20 in EGFR-L858R-driven lung tumors. In lung cancer biopsies, we observed A20 downregulation in EGFR-mutant tumors compared to adjacent healthy tissue, mirroring our previous findings in KRAS-mutant tumors. However, unlike KRAS tumors, tumor-intrinsic A20 deletion significantly prolonged survival in EGFR-driven tumors, accompanied by a reduced tumor burden 18 weeks post-induction. At this stage, control tumors expressing A20 lacked cytotoxic T-cell infiltrates and exhibited a high density of tumor-associated macrophages (TAMs). In contrast, A20-deficient tumors displayed a profoundly anti-tumorigenic microenvironment, enriched with cytotoxic T cells. Mechanistically, A20-deficient tumor cells showed enhanced IFNγ responsiveness, as evidenced by increased STAT1 activation, potentially driving the heightened T-cell recruitment.

Our findings identify A20 as an oncogenic driver in lung cancer. The pronounced T-cell infiltration in A20-deficient tumors, even at later stages, suggests that targeting A20 could be a promising strategy to enhance ICB efficacy in EGFR-mutant lung tumors.