{"database":"GEO","file_versions":[{"headers":{"Content-Type":["application/json"]},"body":{"files":{"Other":["ftp://ftp.ncbi.nlm.nih.gov/geo/series/GSE313nnn/GSE313648/"]},"type":"primary"},"statusCode":"OK","statusCodeValue":200}],"scores":null,"additional":{"omics_type":["Transcriptomics"],"species":["Homo sapiens"],"gds_type":[" Other","Expression profiling by high throughput sequencing"],"full_dataset_link":["https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE313648"],"repository":["GEO"],"entry_type":["GSE"],"additional_accession":[]},"is_claimable":false,"name":"Multimodal profiling of Her2/neu-specific TCR-T cells reveals clonotype-dependent activation programs underlying differential cytotoxic efficacy","description":"Adoptive T cell therapy targeting tumor-associated antigens offers a promising avenue for cancer immunotherapy, yet the mechanisms underlying functional heterogeneity among T cell receptors (TCR) recognizing the same antigen remain poorly understood. Here, we comprehensively profile three Her2/neu-specific TCR constructs using integrated multimodal analysis that combines cytotoxicity assays, single-cell multiomics, bulk transcriptomics, cytokine profiling, and in vivo tumor modeling. Despite identical antigen specificity, the constructs exhibit a functional hierarchy: Construct #3 displays potent cytotoxicity in vitro and potent tumor regression in vivo, whereas Constructs #1 and #2 were less effective. Single-cell proteotranscriptomic analysis shows that tumor cell encounter drives activation of cytotoxic CD8⁺ T effector cells and transdifferentiation of NKT cells into APC-like cells. Interactomics also revealed high communication probability between APC-like NKT cells and CD4⁺ T cells, potentially forming a cooperative activation network that sustains effector function. Bulk transcriptomic and secretomic profiling showed that Construct #3 couples cytolytic gene expression with the secretion of anti-tumor cytokines and effector molecules. Together, these findings establish a mechanistic link between anti-Her2/neu TCR-driven transcriptional programming and therapeutic efficacy, illustrating how multi-omic approaches can inform the rational design of potent TCR therapies for solid tumors.","dates":{"publication":"2026/05/04"},"accession":"GSE313648","cross_references":{"GSM":["GSM9371702"],"GPL":["34281"],"GSE":["313648"],"taxon":["Homo sapiens"]}}