{"doi":"10.1101/2024.02.12.579184","title":"Disrupting CD38-driven T cell dysfunction restores sensitivity to cancer immunotherapy","abstract":"A central problem in cancer immunotherapy with immune checkpoint blockade (ICB) is the development of resistance, which affects 50% of patients with metastatic melanoma 1,2 . T cell exhaustion, resulting from chronic antigen exposure in the tumour microenvironment, is a major driver of ICB resistance 3 . Here, we show that CD38, an ecto-enzyme involved in nicotinamide adenine dinucleotide (NAD + ) catabolism, is highly expressed in exhausted CD8 + T cells in melanoma and is associated with ICB resistance. Tumour-derived CD38 hi CD8 + T cells are dysfunctional, characterised by impaired proliferative capacity, effector function, and dysregulated mitochondrial bioenergetics. Genetic and pharmacological blockade of CD38 in murine and patient-derived organotypic tumour models (MDOTS/PDOTS) enhanced tumour immunity and overcame ICB resistance. Mechanistically, disrupting CD38 activity in T cells restored cellular NAD + pools, improved mitochondrial function, increased proliferation, augmented effector function, and restored ICB sensitivity. Taken together, these data demonstrate a role for the CD38-NAD + axis in promoting T cell exhaustion and ICB resistance, and establish the efficacy of CD38 directed therapeutic strategies to overcome ICB resistance using clinically relevant, patient-derived 3D tumour models.","journal":"bioRxiv (Cold Spring Harbor Laboratory)","year":2024,"id":1254,"datarank":0.2904806749276476,"base_score":1.791759469228055,"endowment":1.791759469228055,"self_citation_contribution":0.26876392038420827,"citation_network_contribution":0.021716754543439378,"self_endowment_contribution":0.26876392038420827,"citer_contribution":0.021716754543439378,"corpus_percentile":null,"corpus_rank":null,"citation_count":5,"citer_count":1,"citers_with_citation_signal":1,"citers_with_endowment":1,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.0453,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2024-02-14","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":15967,"name":"Angelina M. 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