{"doi":"10.1093/jimmun/vkaf283.439","title":"Pediatric Acute Myeloid Leukemia-associated S100A9 Drives T Cell Dysfunction 2533","abstract":"Abstract Description T cell-based immunotherapies have therapeutic efficacy lymphoid leukemia settings yet remain unsuccessful in the treatment of myeloid-associated malignancies. We hypothesized that differences in the lymphoid versus myeloid tumor microenvironment were impacting on the ability of T cells to respond to immunotherapeutic strategies. Indeed, we observed phenotypic and epigenetic differences in CD8 T cells from ALL versus AML patients, which were recapitulated in healthy T cells exposed to AML patient plasma. AML patients had significantly decreased percentages of naïve CD8 T cells with an increased terminally differentiated effector memory T cell population. In addition, AML patient-derived CD8 T cells had significant differences in DNA methylation patterns with increased methylation of lipid metabolism and T cell activation genes and decreased methylation in genes associated with innate immune inflammation signatures compared to ALL patient-derived samples. Investigation into immunosuppressive factors within the patient-derived plasma revealed that S100A9 is uniquely elevated in AML as compared to ALL or healthy controls. Exposure of healthy T cells to S100A9 protein or AML serum induced a dysfunctional terminal effector phenotype, as demonstrated by a significant shift in metabolic potential, blunted cytotoxicity, and limited proliferation. These results provide mechanistic insight into the impact of suppressive tumor microenvironments on limiting T cell-based immunotherapy. Funding Sources This work was supported by the National Institutes of Health (R01CA237311, K08CA279926), Alex’s Lemonade Stand Young Investigator Award, and the American Lebanese Syrian Associated Charities (ALSAC). Topic Categories Tumor Immunology: Cellular Responses and Tumor Microevironment (TIME)","journal":"The Journal of Immunology","year":2025,"id":582246,"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":0,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9487,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2025-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":1494039,"name":"Tyler Bruno","orcid":"0000-0003-3110-6708","position":1,"is_corresponding":false},{"id":1364232,"name":"Tian Mi","orcid":null,"position":2,"is_corresponding":false},{"id":1441342,"name":"Paulina Velasquez","orcid":null,"position":3,"is_corresponding":false},{"id":609796,"name":"Swati Naik","orcid":"0000-0001-9979-7360","position":4,"is_corresponding":false},{"id":271009,"name":"Shanta Alli","orcid":"0000-0003-1692-1616","position":5,"is_corresponding":false},{"id":1194750,"name":"Tae Gun Kang","orcid":"0000-0002-2997-9887","position":6,"is_corresponding":false},{"id":1014691,"name":"Zhiyuan You","orcid":"0000-0001-9833-7485","position":7,"is_corresponding":false},{"id":1195041,"name":"Anoop Babu Vasandan","orcid":null,"position":8,"is_corresponding":false},{"id":461630,"name":"Deanna Langfitt","orcid":"0000-0003-0941-5360","position":9,"is_corresponding":false},{"id":927960,"name":"Matthew Lear","orcid":"0000-0002-9767-2115","position":10,"is_corresponding":false},{"id":3653,"name":"Stephen Gottschalk","orcid":"0000-0003-3991-7468","position":11,"is_corresponding":false},{"id":110364,"name":"Hongbo Chi","orcid":"0000-0002-9997-2496","position":12,"is_corresponding":false},{"id":105446,"name":"Thirumala‐Devi Kanneganti","orcid":"0000-0002-6395-6443","position":13,"is_corresponding":false},{"id":271005,"name":"Caitlin C. Zebley","orcid":"0000-0002-8419-4660","position":14,"is_corresponding":false},{"id":250684,"name":"Ben Youngblood","orcid":"0000-0002-1261-9957","position":15,"is_corresponding":false},{"id":684002,"name":"Grace Ward","orcid":"0000-0003-4404-7727","position":0,"is_corresponding":true}],"reference_count":0,"raw_metadata":null,"created_at":"2026-07-19T02:58:55.657290Z","pmid":null,"pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}