Neoadjuvant anti-4-1BB confers protection against spontaneous metastasis through low-affinity intratumor CD8 + T cells in triple-negative breast cancer
Rattachement africain : us, sg, gb, cn. Niveau de preuve : code pays fourni par la source.
Le résumé fourni par la source
ABSTRACT Neoadjuvant immunotherapy seeks to harness the primary tumor as a source of relevant tumor antigens to enhance systemic anti-tumor immunity through improved immunological surveillance. Despite having revolutionized the treatment of patients with high-risk early-stage triple-negative breast cancer (TNBC), a significant portion of patients remain unresponsive and succumb to metastatic recurrence post-treatment. Here, we found that optimally scheduled neoadjuvant administration of anti-4-1BB monotherapy was able to counteract metastases and prolong survival following surgical resection. Phenotypic and transcriptional profiling revealed enhanced 4-1BB expression on tumor-infiltrating intermediate (T int ), relative to progenitor (T prog ) and terminally exhausted (T term ) T cells. Furthermore, T int was enriched in low-affinity T cells. Treatment with anti-4-1BB drove clonal expansion of T int , with reduced expression of tissue-retention marker CD103 in T prog . This was accompanied by increased TCR clonotype sharing between paired tumors and pre-metastatic lungs. Further interrogation of sorted intratumor T cells confirmed enhanced T cell egress into circulation following anti-4-1BB treatment. In addition, gene signature extracted from anti-4-1BB treated T int was consistently associated with improved clinical outcomes in BRCA patients. Combinatorial neoadjuvant anti-4-1BB and ablation of tumor-derived CXCL16 resulted in enhanced therapeutic effect. These findings illustrate the intratumor changes underpinning the efficacy of neoadjuvant anti-4-1BB, highlighting the reciprocity between local tissue-retention and distant immunologic fortification, suggesting treatment can reverse the siphoning of intratumor T cells to primary tumor, enabling redistribution to distant tissues and subsequent protection against metastases.
Ce résumé expose les affirmations des auteurs. BNTIC ne l’interprète pas comme une validation indépendante des résultats.
Le contrôle bibliographique ouvert
DOI retrouvé dans Crossref DOI retrouvé, mais le titre doit être comparé manuellement.
- Titre Crossref
- Neoadjuvant anti-4-1BB confers protection against spontaneous metastasis through low-affinity intratumor CD8 <sup>+</sup> T cells in triple-negative breast cancer
- Date Crossref
- 02/02/2025
- Éditeur
- openRxiv
- Type
- posted-content
Ce recoupement confirme des métadonnées liées au DOI. Il ne confirme ni la méthode ni les conclusions de l’étude, et il ne compte pas comme une seconde source scientifique indépendante.
Où se fait cette recherche
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Duke University Department of Integrative Immunobiology pays non établi dans la noticeUniversité ou école supérieure
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Agency for Science Singapore Immunology Network pays non établi dans la noticeOrganisme public
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Institute of Molecular and Cell Biology pays non établi dans la noticeStructure de recherche
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TC Biopharm (United Kingdom) pays non établi dans la noticeEntreprise
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Ltd. (China) TCR CURE Biopharma Technology Co. pays non établi dans la noticeEntreprise
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Duke Kunshan University pays non établi dans la noticeUniversité ou école supérieure
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Duke-NUS Medical School pays non établi dans la noticeUniversité ou école supérieure
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Singapore Immunology Network pays non établi dans la noticeStructure de recherche
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TCRCure Biopharma pays non établi dans la noticeInstitution
Department of Integrative Immunobiology — Duke University, Singapore Immunology Network — Agency for Science et Institute of Molecular and Cell Biology, avec 6 autres affiliations.
Une affiliation ne permet pas de déduire la nationalité d’un auteur.