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Updated: May 5, 2026
Multiplexed Immunofluorescence Analysis and Quantification of Intratumoral PD-1+ Tim-3+ CD8+ T Cells
Published on: February 8, 2018
Spatial transcriptomics reveals tryptophan metabolism restricting maturation of intratumoral tertiary lymphoid
Zhonghui Tang1, Yinqi Bai2, Qi Fang3
1Advanced Medical Technology Center, The First Affiliated Hospital, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou 510080, China; Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou 510080, China.
Abstract:
Tertiary lymphoid structures (TLSs) are ectopic lymphoid aggregates found in numerous cancers, often linked to enhanced immunotherapy responses and better clinical outcomes. However, the factors driving TLS maturation are not fully understood. Using near single-cell spatial transcriptomic mapping, we comprehensively profile TLSs under various maturation stages and their microenvironment in hepatocellular carcinoma (HCC). Based on their developmental trajectories, we classify immature TLSs into two groups: conforming and deviating TLSs. Our findings indicate that conforming TLSs, similar to mature TLSs, possess a niche function for immunotherapy responses, while deviating TLSs do not. We discover that the tryptophan-enriched metabolic microenvironment shaped by malignant cells contributes to the deviation of TLS maturation. Inhibiting tryptophan metabolism promotes intratumoral TLS maturation and enhances tumor control, synergizing with anti-PD-1 treatments. Therefore, promoting TLS maturation represents a potential strategy to improve antitumor responses and immunotherapy outcomes.
Insights
Tertiary lymphoid structures (TLSs) in liver cancer can be immature. Targeting tryptophan metabolism promotes TLS maturation, enhancing anti-PD-1 immunotherapy and tumor control.
Area of Science:
- Immunology
- Oncology
- Systems Biology
Background:
- Tertiary lymphoid structures (TLSs) are immune cell aggregates in tumors, associated with better cancer outcomes and immunotherapy efficacy.
- The developmental pathways and factors influencing TLS maturation remain incompletely understood, particularly in hepatocellular carcinoma (HCC).
Purpose of the Study:
- To comprehensively profile TLSs and their microenvironment across different maturation stages in HCC using spatial transcriptomics.
- To identify distinct developmental trajectories of immature TLSs and their functional implications for immunotherapy.
Main Methods:
- Near single-cell spatial transcriptomic mapping of TLSs and their surrounding microenvironment in HCC.
- Classification of immature TLSs based on developmental trajectories into 'conforming' and 'deviating' subtypes.
- In vivo experiments involving inhibition of tryptophan metabolism and combination with anti-PD-1 therapy.
Main Results:
- Immature TLSs were classified into conforming and deviating types, with conforming TLSs exhibiting functional similarity to mature TLSs in supporting immunotherapy.
- A tryptophan-enriched metabolic microenvironment, driven by malignant cells, was identified as a key factor promoting TLS maturation deviation.
- Inhibition of tryptophan metabolism enhanced intratumoral TLS maturation, improved tumor control, and synergized with anti-PD-1 immunotherapy.
Conclusions:
- Conforming TLSs are functionally relevant for immunotherapy responses, whereas deviating TLSs are not.
- Modulating the tumor microenvironment, specifically by targeting tryptophan metabolism, can promote TLS maturation.
- Enhancing TLS maturation presents a promising therapeutic strategy to improve antitumor immunity and clinical outcomes in HCC patients undergoing immunotherapy.
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