Tertiary Lymphoid Structures (TLS) in Cancer: Key Insights from Science Review and Empowerment by ANT BIO PTE. LTD. Multiplex IHC Kits

Tertiary lymphoid structures (TLS), as specialized ectopic lymphoid aggregates emerging within non-lymphoid tissues during chronic inflammation or tumorigenesis, have become a pivotal focus in cancer immunology research. These structures recapitulate the architectural and functional features of secondary lymphoid organs, orchestrating local anti-tumor immune responses by recruiting and activating diverse immune cell populations. A comprehensive review titled "Tertiary lymphoid structures in cancer" published inScience (2022) systematically elaborates on the heterogeneity of TLS in terms of localization, maturation, cellular composition, and molecular characteristics, highlighting their critical role in shaping the tumor immune microenvironment and influencing therapeutic responses. The precise characterization of TLS heterogeneity relies heavily on advanced multiplex imaging techniques, and ANT BIO PTE. LTD.'s multiplex fluorescence IHC kits (Absin product line) provide a powerful tool for in-depth exploration of TLS biology, enabling researchers to decipher the complex immune landscape within TLS and accelerate the development of TLS-targeted cancer immunotherapies.

1. Literature Information

Title: Tertiary lymphoid structures in cancer

Journal: Science

Publication Date: 7 January 2022

Volume & Issue: Vol 375, Issue 6576

DOI: 10.1126/science.abf9419

Authors: Ton N. Schumacher, Daniela S. Thommen

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2. Research Background

Cancer immunotherapy has revolutionized the treatment paradigm for various malignancies, but its efficacy is often limited by the complexity and immunosuppressive nature of the tumor microenvironment (TME). TLS, as ectopic lymphoid structures formed in the TME, have emerged as key regulators of anti-tumor immunity. Unlike primary and secondary lymphoid organs, TLS develop de novo at sites of chronic immune stimulation, such as tumor tissues, and play a crucial role in initiating and sustaining local immune responses against tumors. However, TLS exhibit substantial heterogeneity in their structural organization, cellular composition, and functional capacity, which directly impacts their prognostic and therapeutic implications. Clarifying the heterogeneous characteristics of TLS and their regulatory mechanisms in cancer is essential for optimizing immunotherapeutic strategies and improving patient outcomes. ThisScience review synthesizes current knowledge on TLS biology, providing a comprehensive framework for understanding their role in cancer progression and immunotherapy.

3. Core Insights from the Review: Heterogeneity of TLS in Cancer

The review systematically dissects the heterogeneity of TLS in cancer from multiple dimensions, emphasizing that the structural and functional diversity of TLS is closely associated with tumor progression and therapeutic response. The core insights are summarized as follows:

3.1 Localization Heterogeneity: Intratumoral vs. Peritumoral TLS

TLS in cancer can be classified into two main subtypes based on their localization: intratumoral TLS (located within the tumor parenchyma) and peritumoral TLS (located at the tumor margin). Intratumoral TLS are directly embedded in the tumor tissue, enabling close interaction with tumor cells and the surrounding TME. In contrast, peritumoral TLS are situated at the interface between the tumor and normal tissue, potentially serving as a barrier to tumor invasion. The localization of TLS correlates with their functional capacity and prognostic value—intratumoral TLS, in particular, have been associated with better clinical outcomes in multiple cancer types, as they facilitate direct immune surveillance of tumor cells.

3.2 Maturation Heterogeneity: Primary vs. Secondary Follicles

TLS exhibit distinct stages of maturation, ranging from immature lymphoid aggregates to fully mature secondary follicles. Primary follicle-like TLS contain follicular dendritic cells (FDCs) but lack active germinal center (GC) reactions, limiting their ability to generate robust adaptive immune responses. In contrast, secondary follicle-like TLS possess well-developed GCs, where B cells undergo somatic hypermutation and affinity maturation, and T cells are efficiently activated. Mature TLS with active GCs are associated with enhanced anti-tumor immunity, as they support the generation of tumor-specific B and T cells. The maturation status of TLS is thus a critical determinant of their functional relevance in cancer.

3.3 Cellular Composition Heterogeneity: Diverse Immune and Stromal Cell Populations

TLS are composed of a complex mixture of immune and stromal cells, whose composition varies significantly across different TLS subtypes. Key cellular components include:

•         B Cells: Encompassing naive, mature, memory, and plasma B cells. Within mature TLS, B cells in GCs undergo clonal expansion and differentiation, producing tumor-specific antibodies.

•         T Cells: Including naive T cells, cytotoxic T lymphocytes (CTLs), dysfunctional T cells, T helper cell subsets (TH1, TH2, TH17), follicular helper T cells (TFH), and regulatory T cells (Tregs). The balance between effector T cells (e.g., CTLs, TH1) and immunosuppressive T cells (e.g., Tregs) within TLS dictates the overall anti-tumor immune tone.

•         Dendritic Cells (DCs): Comprising DC-LAMP-positive mature DCs and myeloid-derived suppressor cells (MDSCs). Mature DCs within TLS efficiently present tumor antigens to T cells, initiating adaptive immune responses, while MDSCs exert immunosuppressive effects.

•         Stromal Cells: Including follicular dendritic cells (FDCs) and fibroblastic reticular cells (FRCs), which provide structural support and secrete cytokines/chemokines that regulate TLS formation and immune cell recruitment. Local substitutes for FDCs and FRCs may also exist in immature TLS.

3.4 Molecular Characteristics: Cytokines, Chemokines, and Clonality Features

The molecular profile of TLS is a key driver of their formation and function. Critical molecular characteristics include:

•         Cytokines and Chemokines: TLS formation and immune cell recruitment are orchestrated by a network of cytokines (e.g., TNF-α, IL-23) and chemokines (e.g., CXCL13, CCL21), which guide the migration and activation of immune cells to the TLS niche.

•         Hypermutation and AID Expression: B cells within mature TLS GCs exhibit high rates of somatic hypermutation, driven by the expression of activation-induced cytidine deaminase (AID), which is essential for antibody affinity maturation.

•         BCR and TCR Clonality: TLS contain clonally expanded B and T cells, indicating antigen-driven immune responses. The diversity and specificity of B cell receptors (BCRs) and T cell receptors (TCRs) within TLS reflect the breadth of anti-tumor immune recognition.

•         Vascular and Stromal Markers: High endothelial venules (HEVs) within TLS facilitate lymphocyte recruitment, while stromal components secrete extracellular matrix molecules that support TLS architecture.

4. Product Empowerment: The Critical Role of ANT BIO PTE. LTD.'s Multiplex IHC Kits in TLS Research

The in-depth characterization of TLS heterogeneity requires high-resolution imaging techniques that can simultaneously detect multiple cellular and molecular markers in situ. ANT BIO PTE. LTD.'s multiplex fluorescence IHC kits (Absin product line) provide an indispensable tool for TLS research, enabling the precise identification, localization, and functional analysis of diverse cell populations within TLS.

4.1 Core Products and Their Application Value in TLS Research

4.2 Technical Value in Deciphering TLS Heterogeneity

TLS heterogeneity, characterized by diverse localization, maturation, and cellular composition, poses a significant challenge for in situ analysis. ANT BIO PTE. LTD.'s multiplex fluorescence IHC kits address this challenge by enabling the simultaneous detection of multiple markers on a single tissue section, providing spatial and quantitative information about TLS components. For example, using the 7-color kit (abs50015), researchers can co-stain for B cell markers (CD20), T cell markers (CD3, CD8), DC markers (DC-LAMP), FDC markers (CD21), and GC markers (BCL-6) to comprehensively characterize TLS maturation and cellular composition. This high-dimensional imaging capability allows for the precise classification of TLS subtypes, the analysis of immune cell interactions within TLS, and the correlation of TLS features with clinical outcomes—critical steps for advancing TLS-targeted immunotherapy research.

5. Brand Mission

As a professional supplier of life science reagents, ANT BIO PTE. LTD. is dedicated to providing high-quality, reliable products and comprehensive solutions to empower global life science research. The company's three specialized sub-brands cover the full spectrum of research needs in the life science field: Absin focuses on general reagents and kits, Starter specializes in antibodies, and UA is dedicated to recombinant proteins. Our core mission is to bridge the gap between cutting-edge scientific research and practical applications, accelerate the pace of scientific discovery, and contribute to the advancement of human health and regenerative medicine.

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7. Promotion Information

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8. Disclaimer

This article is AI-compiled and interpreted based on the original review titled "Tertiary lymphoid structures in cancer" published in Science (2022, DOI: 10.1126/science.abf9419). All intellectual property (e.g., images, data) of the original publication shall belong to the journal and the research team. For any infringement, please contact us promptly and we will take immediate action.

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