{"doi":"10.1101/2025.10.17.683070","title":"Molecular Plasticity of T Cells Informs Their Possible Adaptation in 4T1 Tumors","abstract":"ABSTRACT Background The triple-negative breast cancer (TNBC) microenvironment (TME) undergoes progressive reprogramming, transitioning from an early immune-active state to a late immune-suppressed state. While tumor cell plasticity has been extensively studied, the molecular plasticity of T cells in vivo remains poorly defined. Objectives To characterize transcriptional changes in T cells during TNBC progression and identify stage-specific shifts in T cell function, polarization, and antigen-presenting cell (APC)-T cell interactions. Results Transcriptional analysis of T cells from BALB/c mice bearing 4T1 tumors at 1, 3, and 6 weeks revealed a decline in T cell-associated genes from 194 at 1 week to 156 at 6 weeks, with a significant late-stage loss of TCR diversity and contraction of natural killer T (NKT)- and γδ T cell-related transcripts. Cytokine and transcription factor dynamics reflected temporal T cell polarization: early (1 week) IL-12α/β-STAT4 signaling supports CD4 + type 1 T helper cell (Th1) and type 1 CD8 + cytotoxic T cell (Tc1) responses; intermediate (3 weeks) IL-21 and BCL6 expression suggest transient CD8 + cytotoxic follicular T cell (Tfc) skewing; and late (6 weeks) AhR and IL-1β induction reflect interleukin 17/22 producing CD8 + T cell (Tc17/Tc22) transition. Pro-inflammatory cytokines and chemokines increased over time, while immunosuppressive mediators (e.g., IL-10) declined significantly. Antigen-presenting cell (APC)-T cell crosstalk deteriorated at 6 weeks, characterized by a reduction in the expression of co-stimulatory and APC genes. Despite an early dominance of M1-like macrophage signals (e.g., IL-12α/β), persistent expression of arginase 1 (ARG1) and other M2-associated genes indicated a stable tolerogenic niche. Conclusions TNBC progression is characterized by progressive T cell functional decline, narrowing of TCR diversity, impaired APC-T cell interactions, and sustained macrophage-driven immunosuppression. These temporally coordinated immune shifts suggest tumor-driven adaptation toward immune evasion and identify potential windows for stage-specific immunotherapeutic intervention.","journal":"bioRxiv (Cold Spring Harbor Laboratory)","year":2025,"id":578457,"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":0.9605,"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":310397,"name":"Robert H. Newman","orcid":"0000-0002-3865-0266","position":1,"is_corresponding":false},{"id":1232266,"name":"Scott H. Harrison","orcid":"0000-0002-9577-445X","position":2,"is_corresponding":false},{"id":247725,"name":"Roshonda B. Jones","orcid":"0000-0003-1637-3517","position":3,"is_corresponding":false},{"id":1423994,"name":"Perpetua M. Muganda","orcid":"0000-0001-5928-6822","position":4,"is_corresponding":false},{"id":668093,"name":"Bryan L. Holloman","orcid":"0000-0002-9891-9001","position":5,"is_corresponding":false},{"id":1149082,"name":"M. Hossain","orcid":"0009-0003-2489-2672","position":6,"is_corresponding":false},{"id":1377139,"name":"Checo J. Rorie","orcid":"0000-0002-7130-6790","position":7,"is_corresponding":false},{"id":942064,"name":"Misty D. Thomas","orcid":"0000-0001-9039-4098","position":8,"is_corresponding":false},{"id":713263,"name":"Joseph L. Graves","orcid":"0000-0001-8446-1709","position":9,"is_corresponding":false},{"id":364576,"name":"Howard L. Kaufman","orcid":"0000-0003-1131-004X","position":10,"is_corresponding":false},{"id":348242,"name":"Dipongkor Saha","orcid":"0000-0002-9923-5533","position":11,"is_corresponding":false},{"id":1488054,"name":"Md. Iftehimul","orcid":"0000-0001-7847-8774","position":0,"is_corresponding":true}],"reference_count":65,"raw_metadata":null,"created_at":"2026-07-19T02:58:20.638044Z","pmid":"41278869","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":[]}