{"doi":"10.1101/2020.09.03.278309","title":"Single-cell Characterization of Acute Myeloid Leukemia and its Microenvironment Following PD-1 Blockade Based Therapy","abstract":"Abstract Acute myeloid leukemia (AML) and effector cells of immune checkpoint blockade (ICB) therapy co-reside in a complex bone marrow (BM) milieu. The interplay of tumor intrinsic and microenvironment (TME) mechanisms that influences the response to ICB-based therapies in AML have not been elucidated. Here we report our analyses of single cell RNA profiling of more than 127,000 BM cells from healthy donors and relapsed/refractory (R/R) AML patients at pre/post treatment with azacitidine/nivolumab, paired with single cell T cell receptor (TCR) repertoire profiles, to uncover factors impacting response and resistance. Loss of chromosome 7/7q conferred an immunosuppressive TME and was associated with resistance to ICB-based therapy in R/R AML. Our trajectory analysis revealed a continuum of CD8+ T cell phenotypes, characterized by differential expression of granzyme B (GZMB) and GZMK. GZMK expression defined a BM residing memory CD8+ T cell subset with stem-like properties likely an intermediary between naïve and cytotoxic lymphocytes. Responses to ICB-based therapy were primarily driven by novel and expanded T cell clonotypes. Our findings support an adaptable T cell plasticity in response to PD-1 blockade in AML. Disentangling AML cells from their complex, immune-rich microenvironment revealed characteristics that shaped resistance to ICB-based therapy and could inform strategies to target AML vulnerabilities. Significance Determining the cellular and molecular underpinnings of response and resistance to PD-1 blockade based therapy in AML can guide immune-based therapeutic strategies. Our results reveal AML intrinsic characteristics (chromosome 7/7q status and oxidative stressors) and tumor microenvironment to modulate responses to checkpoint blockers. CD8 cells exist in the bone marrow in a continuum with GZMK expression defining a memory, stem-like T cell population that could play a role in response to therapy.","journal":"bioRxiv (Cold Spring Harbor Laboratory)","year":2020,"id":124007,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":3,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.8327,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2020-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":554754,"name":"Dapeng Hao","orcid":"0000-0002-9043-371X","position":1,"is_corresponding":false},{"id":567731,"name":"Katarzyna Tomczak","orcid":"0000-0003-0553-8056","position":2,"is_corresponding":false},{"id":567732,"name":"Praveen Barrodia","orcid":"0000-0001-7932-2325","position":3,"is_corresponding":false},{"id":567733,"name":"Jin S. 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Reville","orcid":"0000-0001-8433-3360","position":5,"is_corresponding":false},{"id":567735,"name":"Zoe Alaniz","orcid":"0000-0002-9424-5417","position":6,"is_corresponding":false},{"id":350113,"name":"Wei Wang","orcid":"0000-0001-6821-4556","position":7,"is_corresponding":false},{"id":14192,"name":"Linghua Wang","orcid":"0000-0001-9380-0266","position":8,"is_corresponding":false},{"id":506559,"name":"Feng Wang","orcid":"0000-0002-9263-1867","position":9,"is_corresponding":false},{"id":368641,"name":"Gheath Alatrash","orcid":"0000-0002-7648-4377","position":10,"is_corresponding":false},{"id":108815,"name":"Koichi Takahashi","orcid":"0000-0002-8027-9659","position":11,"is_corresponding":false},{"id":232859,"name":"Jing Ning","orcid":"0000-0002-5289-331X","position":12,"is_corresponding":false},{"id":568196,"name":"Maomao Ding","orcid":null,"position":13,"is_corresponding":false},{"id":568197,"name":"Jairo T. 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