Decrease of tumoral CD39+CD8+T cells promoted by hypoxia confers resistance to immunotherapy in NSCLC

Abstract Understanding resistance to anti-PD-1 is crucial for the development of reversal strategies. Here, we analyzed a subset of tumor-infiltrating CD8⁺T cells based on the expression of the ATP ectonucleotidase CD39, further explored its spatial distribution being priming as a contributor to anti-PD-1 therapeutic response or resistance. It is interesting that CD39⁺CD8⁺T cells were more enriched in peritumor compared to center, as well as being severed as a potential immuno-responsive biomarker for anti-PD-1 therapy. Correspondingly, it revealed more hypoxia actually existed in central TME, thereby reducing CD39⁺CD8⁺T cells infiltration and dampening the efficacy of anti-PD-1. As supported, multiple in vitro assays demonstrated that absence of CD39 limited functional restore of CD8⁺T cells upon PD-1 blockade. Collectively, we illustrated the hypoxia was involved in establishing an immunosuppressive TME defined by spatial distribution of CD39⁺CD8⁺T cells and consequentially implied a novel approach of resistance to immunotherapy.