Tertiary Lymphoid Structures in Cancer: The Double-Edged Sword Role in Antitumor Immunity and Potential Therapeutic Induction Strategies

The complex tumor microenvironment (TME) plays a vital role in cancer development and dramatically determines the efficacy of immunotherapy. Tertiary lymphoid structures (TLSs) within the TME are well recognized and consist of T cell-rich areas containing dendritic cells (DCs) and B cell-rich areas containing germinal centers (GCs). Accumulating research has indicated that there is a close association between tumor-associated TLSs and favorable clinical outcomes in most types of cancers, though a minority of studies have reported an association between TLSs and a poor prognosis. Overall, the double-edged sword role of TLSs in the TME and potential mechanisms need to be further investigated, which will provide novel therapeutic perspectives for antitumor immunoregulation. In this review, we focus on discussing the main functions of TLSs in the TME and recent advances in the therapeutic manipulation of TLSs through multiple strategies to enhance local antitumor immunity.

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Insights Into Unveiling a Potential Role of Tertiary Lymphoid Structures in Metastasis

Frontiers in Molecular Biosciences ◽

10.3389/fmolb.2021.661516 ◽

2021 ◽

Vol 8 ◽

Author(s):

Rami Mustapha ◽

Kenrick Ng ◽

James Monypenny ◽

Tony Ng

Keyword(s):

Antitumor Immunity ◽

Cancer Metastasis ◽

Potential Role ◽

Cancer Invasiveness ◽

Tertiary Lymphoid Structures ◽

Lymphoid Structures ◽

Cancer Dissemination ◽

Alternative Routes ◽

Biomechanical Factors

Tertiary lymphoid structures (TLSs) develop in non-lymphatic tissue in chronic inflammation and cancer. TLS can mature to lymph node (LN) like structures with germinal centers and associated vasculature. TLS neogenesis in cancer is highly varied and tissue dependent. The role of TLS in adaptive antitumor immunity is of great interest. However, data also show that TLS can play a role in cancer metastasis. The importance of lymphatics in cancer distant metastasis is clear yet the precise detail of how various immunosurveillance mechanisms interplay within TLS and/or draining LN is still under investigation. As part of the tumor lymphatics, TLS vasculature can provide alternative routes for the establishment of the pre-metastatic niche and cancer dissemination. The nature of the cytokine and chemokine signature at the heart of TLS induction can be key in determining the success of antitumor immunity or in promoting cancer invasiveness. Understanding the biochemical and biomechanical factors underlying TLS formation and the resulting impact on the primary tumor will be key in deciphering cancer metastasis and in the development of the next generation of cancer immunotherapeutics.

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IA19 Evaluating the Role of B Cells and Tertiary Lymphoid Structures in Lung Cancer Development and Progression

Journal of Thoracic Oncology ◽

10.1016/j.jtho.2019.12.019 ◽

2020 ◽

Vol 15 (2) ◽

pp. S6

Author(s):

T.C. Bruno

Keyword(s):

Lung Cancer ◽

B Cells ◽

Cancer Development ◽

Tertiary Lymphoid Structures ◽

Lymphoid Structures

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Divergent cancer etiologies drive distinct B cell signatures and tertiary lymphoid structures

10.1101/2020.05.29.123265 ◽

2020 ◽

Author(s):

Ayana T Ruffin ◽

Anthony R Cillo ◽

Tracy Tabib ◽

Angen Liu ◽

Sayali Onkar ◽

...

Keyword(s):

B Cells ◽

Single Cell ◽

Antitumor Immunity ◽

Spatial Organization ◽

Environmental Carcinogens ◽

Transitional State ◽

Rnaseq Data ◽

Tertiary Lymphoid Structures ◽

Lymphoid Structures

AbstractCurrent immunotherapy paradigms aim to reinvigorate CD8+ T cells, but the contribution of humoral immunity to antitumor immunity remains understudied1,2. Head and neck squamous cell carcinoma (HNSCC) is caused by either human papillomavirus (HPV+) or environmental carcinogens (i.e. tobacco and alcohol; HPV–)3,4. Here, we demonstrate that HPV+ HNSCC patients have transcriptional signatures of germinal center (GC) tumor infiltrating B cells (TIL-Bs) and spatial organization of immune cells consistent with GC-like tertiary lymphoid structures (TLS), both of which correlate with favorable outcomes in HNSCC patients. Further, our single-cell RNAseq data also indicate that GC TIL-Bs are characterized by distinct waves of gene expression consistent with dark zone, light zone and a transitional state of GC B cells. High-dimensional spectral flow cytometry permitted in depth characterization of activated, memory and GC TIL-Bs. Further, single cell RNAseq analysis and subsequent protein validation identified a role for semaphorin 4a (Sema4a) in the differentiation of GC TIL-Bs and indicated that expression of Sema4a was enhanced on GC TIL-Bs and within GC-like TLS in the TME. Thus, in contrast to some reports on the detrimental role of TIL-Bs in human tumors, our findings suggest that TIL-Bs play an instrumental role in antitumor immunity5,6. Novel therapeutics to enhance TIL-B responses in HNSCC should be prioritized as a compliment to current T-cell mediated immunotherapies.

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Mature tertiary lymphoid structures in lung adenocarcinoma are associated with better progression free survival

American Journal of Clinical Pathology ◽

10.1093/ajcp/aqab191.317 ◽

2021 ◽

Vol 156 (Supplement_1) ◽

pp. S149-S149

Author(s):

R Obeng ◽

V Parihar ◽

D Alexis ◽

M Behera ◽

T Owonikoko ◽

...

Keyword(s):

Tumor Microenvironment ◽

Lung Adenocarcinoma ◽

Progression Free Survival ◽

Germinal Centers ◽

Disease Stage ◽

Free Survival ◽

Formalin Fixed Paraffin Embedded ◽

Tertiary Lymphoid Structures ◽

Lymphoid Structures ◽

Lymphoid Aggregates

Abstract Introduction/Objective The presence of inducible lymphoid structures known as tertiary lymphoid structures in the tumor microenvironment has been shown to correlate with positive clinical outcome. However, the maturation states of lymphoid aggregates in lung adenocarcinoma are not completely understood. Methods/Case Report Seventy tumor samples from 69 patients diagnosed with lung adenocarcinoma (Stages I to III) between 2013 and 2015 were included in the study. The presence and maturation states of the lymphoid structures within the tumors were evaluated by conventional and 26 samples were further analyzed by multiplexed immunohistochemistry of formalin fixed paraffin embedded tissues and then quantified. Mature lymphoid follicles containing germinal centers were identified by the presence of CD21+ and BCL-6+ cells in an organized configuration within tight clusters of T and B cells. Results (if a Case Study enter NA) Samples with fully mature lymphoid structures (germinal centers) had larger tumors and higher disease stage. The number of mature lymphoid structures correlated with the total number of lymphoid aggregates present in the tumor microenvironment. Additionally, tumor samples with ≥10 mature lymphoid structures had more primary follicles. While there was no difference in overall survival, progression free survival was significantly longer in patients who had ≥10 mature lymphoid structures in comparison with patients who had <10 mature structures. Conclusion In conclusion, a spectrum of lymphoid aggregates in different stages of maturation are present in lung adenocarcinoma. An increase in the number of mature lymphoid structures may be associated with progression free survival in patients with lung adenocarcinoma.

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Immunology of Solid Tumors Beyond Tumor-Infiltrating Lymphocytes: The Role of Tertiary Lymphoid Structures

Biomarkers of the Tumor Microenvironment ◽

10.1007/978-3-319-39147-2_11 ◽

2017 ◽

pp. 259-280

Author(s):

Gert G. G. M. Van den Eynden ◽

Roberto Salgado ◽

Karen Willard-Gallo

Keyword(s):

Solid Tumors ◽

Tumor Infiltrating Lymphocytes ◽

Tertiary Lymphoid Structures ◽

Lymphoid Structures ◽

Infiltrating Lymphocytes

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The role of exosomal lncRNAs in cancer biology and clinical management

Experimental & Molecular Medicine ◽

10.1038/s12276-021-00699-4 ◽

2021 ◽

Author(s):

Wuwen Zhang ◽

Qinshi Wang ◽

Yi Yang ◽

Siyuan Zhou ◽

Ping Zhang ◽

...

Keyword(s):

Clinical Management ◽

Cancer Biology ◽

Cell Communication ◽

Noncoding Rnas ◽

Vital Role ◽

Cancer Development ◽

Cancer Cell Proliferation ◽

Diagnosis And Prognosis ◽

Multiple Processes

AbstractExosomes play a vital role in cell–cell communication within the cancer microenvironment. Exosomal long noncoding RNAs (lncRNAs) are important regulators in cancer development and are involved in multiple processes, including cancer cell proliferation, angiogenesis, metastasis, drug resistance, and immunomodulation. Changes in the levels of exosomal lncRNAs often appear with the occurrence and development of cancer. Therefore, exosomal lncRNAs can be used as biomarkers for cancer diagnosis and prognosis. Exosomal lncRNAs can also indicate the treatment response of patients receiving chemotherapy. Moreover, exosomal lncRNAs are potential therapeutic targets for cancer treatment. In this review, we summarize the role of exosomal lncRNAs in cancer biology as well as in clinical management. A more comprehensive and in-depth understanding of the role of exosomal lncRNAs in cancer may help us better understand the mechanism of cancer development and clinically manage cancer patients.

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