Adaptive resistance to therapeutic PD-1 blockade is associated with upregulation of alternative immune checkpoints

TLDR

Despite strong antitumor activity of PD‑1/PD‑L1 blockade in lung cancer, resistance to these therapies is increasingly observed. The study aims to elucidate mechanisms of adaptive resistance by analyzing the tumor immune microenvironment during anti‑PD‑1 therapy in two fully immunocompetent mouse models of lung adenocarcinoma. The authors analyze the tumor immune microenvironment during anti‑PD‑1 therapy in two fully immunocompetent mouse models of lung adenocarcinoma. Tumors progressing after anti‑PD‑1 therapy show upregulation of alternative checkpoints, especially TIM‑3 on PD‑1‑bound T cells, and combining a TIM‑3 blocker improves survival, indicating TIM‑3 upregulation is a targetable biomarker of adaptive resistance.

Abstract

Abstract Despite compelling antitumour activity of antibodies targeting the programmed death 1 (PD-1): programmed death ligand 1 (PD-L1) immune checkpoint in lung cancer, resistance to these therapies has increasingly been observed. In this study, to elucidate mechanisms of adaptive resistance, we analyse the tumour immune microenvironment in the context of anti-PD-1 therapy in two fully immunocompetent mouse models of lung adenocarcinoma. In tumours progressing following response to anti-PD-1 therapy, we observe upregulation of alternative immune checkpoints, notably T-cell immunoglobulin mucin-3 (TIM-3), in PD-1 antibody bound T cells and demonstrate a survival advantage with addition of a TIM-3 blocking antibody following failure of PD-1 blockade. Two patients who developed adaptive resistance to anti-PD-1 treatment also show a similar TIM-3 upregulation in blocking antibody-bound T cells at treatment failure. These data suggest that upregulation of TIM-3 and other immune checkpoints may be targetable biomarkers associated with adaptive resistance to PD-1 blockade.