{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,28]],"date-time":"2026-09-28T20:52:42Z","timestamp":1790628762753,"version":"4.1.0"},"reference-count":65,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2023,11,27]],"date-time":"2023-11-27T00:00:00Z","timestamp":1701043200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Immunol."],"abstract":"<jats:p>\n                    Cervical cancer is a leading cause of death among women globally, primarily driven by high-risk papillomaviruses. However, the effectiveness of chemotherapy is limited, underscoring the potential of personalized immunotherapies. Patient-derived organoids, which possess cellular heterogeneity, proper epithelial architecture and functionality, and long-term propagation capabilities offer a promising platform for developing viable strategies. In addition to \u03b1\u03b2 T cells and natural killer (NK) cells, \u03b3\u03b4 T cells represent an immune cell population with significant therapeutic potential against both hematologic and solid tumours. To evaluate the efficacy of \u03b3\u03b4 T cells in cervical cancer treatment, we generated patient-derived healthy and cancer ectocervical organoids. Furthermore, we examined transformed healthy organoids, expressing HPV16 oncogenes E6 and E7. We analysed the effector function of\n                    <jats:italic>in vitro<\/jats:italic>\n                    expanded \u03b3\u03b4 T cells upon co-culture with organoids. Our findings demonstrated that healthy cervical organoids were less susceptible to \u03b3\u03b4 T cell-mediated cytotoxicity compared to HPV-transformed organoids and cancerous organoids. To identify the underlying pathways involved in this observed cytotoxicity, we performed bulk-RNA sequencing on the organoid lines, revealing differences in DNA-damage and cell cycle checkpoint pathways, as well as transcription of potential \u03b3\u03b4 T cell ligands. We validated these results using immunoblotting and flow cytometry. We also demonstrated the involvement of BTN3A1 and BTN2A1, crucial molecules for \u03b3\u03b4 T cell activation, as well as differential expression of PDL1\/CD274 in cancer, E6\/E7+ and healthy organoids. Interestingly, we observed a significant reduction in cytotoxicity upon blocking MSH2, a protein involved in DNA mismatch-repair. In summary, we established a co-culture system of \u03b3\u03b4 T cells with cervical cancer organoids, providing a novel\n                    <jats:italic>in vitro<\/jats:italic>\n                    model to optimize innovative patient-specific immunotherapies for cervical cancer.\n                  <\/jats:p>","DOI":"10.3389\/fimmu.2023.1281646","type":"journal-article","created":{"date-parts":[[2023,11,27]],"date-time":"2023-11-27T01:47:45Z","timestamp":1701049665000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":26,"title":["\u03b3\u03b4 T cell-mediated cytotoxicity against patient-derived healthy and cancer cervical 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