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Spatial multi-omics implicate the interaction between Tpex and B cells in tertiary lymphoid structures after
Jingying Huang1, Yahui Chen2, Peng Deng1
1Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University Guangzhou China.
Abstract:
Tertiary lymphoid structures (TLSs) are associated with the efficacy of various oncological therapies. However, the comprehensive spatial TLS pharmacodynamics are largely unclear. Here, we performed multifaceted spatial transcriptomic analysis with whole-transcriptome coverage and single-cell resolution, complemented by the high-throughput spatial proteomics, to thoroughly characterize TLSs in clinical breast cancer samples after neoadjuvant therapy. Notably, spatial multi-omics data identified that precursors of exhausted T cells (Tpex cells) preferentially reside within TLSs. Spatial transcriptomics with TCR-seq revealed the presence of tumor-specific Tpex cells inside TLSs and their clonally related terminally differentiated effector T cells outside TLSs. B cells are nearest neighbors of Tpex cells in TLSs and B cells promote invigoration of Tpex cells via ICOSL-ICOS and CD86-CD28 interactions within TLSs. These findings extend the current understanding of TLS spatial architecture and highlight a therapy-induced evolution of anti-tumor immune responses driven by the interaction between Tpex cells and B cells within TLSs.
Insights
Tertiary lymphoid structures (TLSs) harbor precursors of exhausted T cells (Tpex cells) in breast cancer. Within TLSs, B cells invigorate Tpex cells, driving anti-tumor immunity after therapy.
Area of Science:
- Immunology
- Cancer Biology
- Spatial Biology
Background:
- Tertiary lymphoid structures (TLSs) are crucial in anti-tumor immunity and therapy response.
- The precise spatial organization and function of TLSs, especially after neoadjuvant therapy, remain incompletely understood.
Purpose of the Study:
- To comprehensively characterize the spatial pharmacodynamics of TLSs in breast cancer patients post-neoadjuvant therapy.
- To elucidate the cellular composition and interactions within TLSs at single-cell resolution.
Main Methods:
- Multifaceted spatial transcriptomic analysis with whole-transcriptome coverage and single-cell resolution.
- High-throughput spatial proteomics.
- T-cell receptor sequencing (TCR-seq) integrated with spatial transcriptomics.
Main Results:
- Precursors of exhausted T cells (Tpex cells) were identified to preferentially reside within TLSs.
- Tumor-specific Tpex cells were found within TLSs, with clonally related effector T cells located outside.
- B cells were identified as nearest neighbors to Tpex cells, facilitating Tpex cell invigoration through ICOSL-ICOS and CD86-CD28 interactions.
Conclusions:
- Spatial multi-omics reveals a distinct localization of Tpex cells within TLSs.
- B cell interactions within TLSs are critical for Tpex cell invigoration and anti-tumor immune response.
- These findings highlight therapy-induced immune evolution within the tumor microenvironment.
