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Neoadjuvant anti-4-1BB confers protection against spontaneous metastasis through low-affinity intratumor CD8 + T cells in triple-negative breast cancer
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Neoadjuvant anti-4-1BB confers protection against spontaneous metastasis through low-affinity intratumor CD8 + T cells in triple-negative breast cancer
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Journal Article
Neoadjuvant anti-4-1BB confers protection against spontaneous metastasis through low-affinity intratumor CD8 + T cells in triple-negative breast cancer
2025
Overview
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
), relative to progenitor (T
) and terminally exhausted (T
) T cells. Furthermore, T
was enriched in low-affinity T cells. Treatment with anti-4-1BB drove clonal expansion of T
, with reduced expression of tissue-retention marker CD103 in T
. 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
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.
Publisher
Cold Spring Harbor Laboratory Press,Cold Spring Harbor Laboratory
Subject
