Clinical and molecular features of acquired resistance to immunotherapy in non-small cell lung cancer
Menée à l'aide notamment de lignées cellulaires, de modèles murins et de données portant sur 1 201 patients atteints d'un cancer du poumon non à petites cellules traité par anti-PD-1, cette étude identifie les caractéristiques moléculaires et cliniques associées à l'acquisition d'une résistance aux inhibiteurs de points de contrôle immunitaires
Although immunotherapy with PD-(L)1 blockade is routine for lung cancer, little is known about acquired resistance. Among 1,201 patients with non-small cell lung cancer (NSCLC) treated with PD-(L)1 blockade, acquired resistance is common, occurring in >60% of initial responders. Acquired resistance shows differential expression of inflammation and interferon (IFN) signaling. Relapsed tumors can be separated by upregulated or stable expression of IFN
γ response genes. Upregulation of IFNγ response genes is associated with putative routes of resistance characterized by signatures of persistent IFN signaling, immune dysfunction, and mutations in antigen presentation genes which can be recapitulated in multiple murine models of acquired resistance to PD-(L)1 blockade after in vitro IFNγ treatment. Acquired resistance to PD-(L)1 blockade in NSCLC is associated with an ongoing, but altered IFN response. The persistently inflamed, rather than excluded or deserted, tumor microenvironment of acquired resistance may inform therapeutic strategies to effectively reprogram and reverse acquired resistance.
Cancer Cell , article en libre accès, 2023