Tertiary lymphoid structures, drivers of the anti‐tumor responses in human cancers

Abstract

The characterization of the microenvironment of human tumors led to the description of tertiary lymphoid structures (TLS) characterized by mature dendritic cells in a T-cell zone adjacent to B-cell follicle including a germinal center. TLS represent sites of lymphoid neogenesis that develop in most solid cancers. Analysis of the current literature shows that the TLS presence is associated with a favorable clinical outcome for cancer patients, regardless of the approach used to quantify TLS and the stage of the disease. Using several approaches that combine immunohistochemistry, gene expression assays, and flow cytometry on large series of lung tumors, our work demonstrated that TLS are important sites for the initiation and/or maintenance of the local and systemic T- and B-cell responses against tumors. Surrounded by high endothelial venules, they represent a privileged area for the recruitment of lymphocytes into tumors and generation of central-memory T and B cells that circulate and limit cancer progression. TLS can be considered as a novel biomarker to stratify the overall survival risk of untreated cancer patients and as a marker of efficient immunotherapies. The induction and manipulation of cancer-associated TLS using drug agonists and/or biotherapies should open new avenues to treat cancer patients.

Lymphatic vessel density is associated with CD8+ T cell infiltration and immunosuppressive factors in human melanoma

“…TLS are of increasing interest in tumor immunology because they are often associated with anti-tumor T cell responses and favorable prognosis of cancer patients. 53 Although high endothelial venules (HEVs) have been described in primary melanoma and have been linked to good clinical outcome, 54 , 55 conflicting results exist in regard to the presence of TLSs in primary melanoma, in spite of the fact that the latter frequently contain HEVs. 56 , 57 While we found a positive association between lymphatics and CD19 + cells in metastatic LNs, we did not detect many B cell clusters in the tumor samples examined here.…”

CXCL13-producing TFH cells link immune suppression and adaptive memory in human breast cancer

“…It is required for early recruitment of lymphoid tissue inducer cells and functions upstream of other early signals, including the lymphotoxin-β receptor (8). De novo TLS formation in chronically inflamed tissues has been correlated with allograft rejection, autoimmune disease progression (9), and improved cancer outcomes (10). Influenza-induced TLS in the lung (but not nearby secondary lymphoid organs) and the subsequent generation of resident memory B cells were responsible for limiting virus escape after infection (11).…”

Potential of Cells and Cytokines/Chemokines to Regulate Tertiary Lymphoid Structures in Human Diseases

“…Moreover, B cells contribute to local immune responses to persisting autoantigens by producing proinflammatory cytokines, chemokines and growth factors, all of which are crucial for TLS formation. Also, B cells co-operate with CD8 + tumor-infiltrating lymphocytes to promote anticancer immunity and act as new prognostic biomarkers for cancer survival (3637). …”

“…Both costimulatory ligand expression by DCs and T cell proliferation in tumor-associated TLS increase upon Treg cell depletion, leading to tumor destruction (3). TLS develop in most solid cancers and correlate with a favorable clinical outcome for cancer patients, regardless of the stage of disease (36). Thus, tumor-associated-TLS promote anti-tumor responses.…”