Lymphodepleting preconditioning impairs host antitumor immunity induced by adoptive T cell therapy in mouse models

Journal article

Adoptive T cell therapy (ACT) is effective against hematologic cancers, but the mechanisms underlying durable responses in solid tumors remain unclear. We show that adoptively transferred CD8+ T cells that eradicate established murine tumors promote expansion of host CD8+ T cells exhibiting tumor-reactive and tissue-resident phenotypes that contribute to tumor elimination. Mechanistically, tumor necrosis factor (TNF) from transferred cells induces dendritic cell (DC)-dependent expansion of host CD8+ T cells, conferring protection against ACT-resistant tumor cells lacking the targeted antigen. Lymphodepleting preconditioning promotes expansion of transferred cells and primary tumor eradication but impairs host antitumor immunity and abrogates protection against ACT-resistant tumors. In human tumors, increased TNF/DC/CD8+ T cell profiles correlate with favorable ACT responses and improved survival. These findings reveal a TNF-dependent interplay between transferred and host CD8+ T cells underlying durable antitumor immunity that is impaired by lymphodepleting preconditioning in mouse models, suggesting an underappreciated mechanism of ACT resistance.

Authors: Figueroa, D; Vega, JP; Hernández-Oliveras, A; Ardiles, F; Hidalgo, S

• Publication status: Published
• Peer review status: Peer reviewed
• Publisher: Nature Research
• Journal: Nature Communications
• Volume: 17
• Issue: 1
• Article number: 4337
• Publication date: 2026-03-31
• Acceptance date: 2026-03-11
• DOI: 10.1038/s41467-026-71082-y
• EISSN: 2041-1723
• ISSN: 2041-1723
• Language: English
• Keywords: CD8; Cytotoxic T cell; Immunity; Adoptive cell transfer; T cell; Tumor necrosis factor alpha; Immune system; Cell therapy