Dataset Information

Tumor-associated neutrophils (TANs) in human carcinoma-draining lymph nodes: a novel TAN compartment.

ABSTRACT:

Objectives

The role of tumor-associated neutrophils (TANs) in the nodal spread of cancer cells remains unexplored. The present study evaluates the occurrence and clinical significance of human nodal TANs.

Methods

The relevance, derivation, phenotype and interactions of nodal TANs were explored via a large immunohistochemical analysis of carcinoma-draining lymph nodes, and their clinical significance was evaluated on a retrospective cohort of oral squamous cell carcinomas (OSCC). The tumor-promoting function of nodal TAN was probed in the OSCC TCGA dataset combining TAN and epithelial-to-mesenchymal transition (EMT) signatures.

Results

The pan-carcinoma screening identified a consistent infiltration (59%) of CD66b⁺ TANs in tumor-draining lymph nodes (TDLNs). Microscopic findings, including the occurrence of intra-lymphatic conjugates of TANs and cancer cells, indicate that TANs migrate through lymphatic vessels. In vitro experiments revealed that OSCC cell lines sustain neutrophil viability and activation via release of GM-CSF. Moreover, by retrospective analysis, a high CD66b⁺ TAN density in M-TDLNs of OSCC (n = 182 patients) predicted a worse prognosis. The analysis of the OSCC-TCGA dataset unveiled that the expression of a set of neutrophil-specific genes in the primary tumor (PT) is highly associated with an EMT signature, which predicts nodal spread. Accordingly, in the PT of OSCC cases, CD66b⁺TANs co-localised with PDPN⁺S100A9^- EMT-switched tumor cells in areas of lymphangiogenesis. The pro-EMT signature is lacking in peripheral blood neutrophils from OSCC patients, suggesting tissue skewing of TANs.

Conclusion

Our findings are consistent with a novel pro-tumoral TAN compartment that may promote nodal spread via EMT, through the lymphatics.

SUBMITTER: Lonardi S

PROVIDER: S-EPMC7886597 | biostudies-literature | 2021

REPOSITORIES: biostudies-literature

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Publications

Tumor-associated neutrophils (TANs) in human carcinoma-draining lymph nodes: a novel TAN compartment.

Lonardi Silvia S Missale Francesco F Calza Stefano S Bugatti Mattia M Vescovi Raffaella R Debora Bresciani B Uppaluri Ravindra R Egloff Ann Marie AM Mattavelli Davide D Lombardi Davide D Benerini Gatta Luisa L Marini Olivia O Tamassia Nicola N Gardiman Elisa E Cassatella Marco A MA Scapini Patrizia P Nicolai Piero P Vermi William W

Clinical & translational immunology 20210216 2

<h4>Objectives</h4>The role of tumor-associated neutrophils (TANs) in the nodal spread of cancer cells remains unexplored. The present study evaluates the occurrence and clinical significance of human nodal TANs.<h4>Methods</h4>The relevance, derivation, phenotype and interactions of nodal TANs were explored <i>via</i> a large immunohistochemical analysis of carcinoma-draining lymph nodes, and their clinical significance was evaluated on a retrospective cohort of oral squamous cell carcinomas (O ...[more]

PMID: 33643653

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Project description:Tumor-draining lymph nodes (TDLNs) are the first organs where the metastatic spread of different types of cancer, including head and neck cancer (HNC), occurs and have therefore high prognostic relevance. Moreover, first anti-cancer immune responses have been shown to be initiated in such LNs via tumor-educated myeloid cells. Among myeloid cells present in TDLNs, neutrophils represent a valuable population and considerably participate in the activation of effector lymphocytes there. Tumor-supportive or tumor-inhibiting activity of neutrophils strongly depends on the surrounding microenvironment. Thus, type I interferon (IFN) availability has been shown to prime anti-tumor activity of these cells. In accordance, mice deficient in type I IFNs show elevated tumor growth and metastatic spread, accompanied by the pro-tumoral neutrophil bias. To reveal the mechanism responsible for this phenomenon, we have studied here the influence of defective type I IFN signaling on the immunoregulatory activity of neutrophils in TDLNs. Live imaging of such LNs was performed using two-photon microscopy in a transplantable murine HNC model. CatchupIVM-red and Ifnar1-/- (type I IFN receptor- deficient) CatchupIVM-red mice were used to visualize neutrophils and to assess their interaction with T-cells in vivo. We have evaluated spatiotemporal patterns of neutrophil/T-cell interactions in LNs in the context of type I interferon receptor (IFNAR1) availability in tumor-free and tumor-bearing animals. Moreover, phenotypic and functional analyses were performed to further characterize the mechanisms regulating neutrophil immunoregulatory capacity. We demonstrated that inactive IFNAR1 leads to elevated accumulation of neutrophils in TDLNs. However, these neutrophils show significantly impaired capacity to interact with and to stimulate T-cells. As a result, a significant reduction of contacts between neutrophils and T lymphocytes is observed, with further impairment of T-cell proliferation and activation. This possibly contributes to the enhanced tumor growth in Ifnar1-/- mice. In agreement with this, IFNAR1-independent activation of downstream IFN signaling using IFN-λ improved the immunostimulatory capacity of neutrophils in TDLNs and contributed to the suppression of tumor growth. Our results suggest that functional type I IFN signaling is essential for neutrophil immunostimulatory capacity and that stimulation of this signaling may provide a therapeutic opportunity in head and neck cancer patients.

Dataset Information

Tumor-associated neutrophils (TANs) in human carcinoma-draining lymph nodes: a novel TAN compartment.

Objectives

Methods

Results

Conclusion

Publications

Tumor-associated neutrophils (TANs) in human carcinoma-draining lymph nodes: a novel TAN compartment.

Similar Datasets

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