The efficacy of immune checkpoint blockade (ICB) in NSCLC depends on the tumor mutational burden (TMB). However, a fraction of patients with high TMB and predicted immunogenic neoantigens (neoAgs) do not respond. Here we show that in a model of highly mutated NSCLC, cross-presenting cDC1s are required to induce broad effector CD8+ T cell responses to both strong and weak endogenous neoAgs. Importantly, cDC1 amplification by Flt3L increases immunogenicity of MHC class-I neoepitopes and promotes tumor regression, whilst PD-L1 blockade is ineffective. cDC1 density correlates to CD8+ T cell scores and prognosis, particularly in hypermutated human NSCLC. Single-cell RNA sequencing reveals the molecular determinants of Flt3L-therapy including expansion of immunogenic lung cDC1 and proliferation of cytotoxic CD8+ T cells with reduced exhaustion. We conclude that boosting cDC1 activity is critical to leverage neoAgs content for therapeutic advantage in hypermutated lung tumors that do not respond to ICB.
