Dataset Information

High Numbers and Densities of PD1+ T-Follicular Helper Cells in Triple-Negative Breast Cancer Draining Lymph Nodes Are Associated with Lower Survival.

ABSTRACT: Breast cancer tumor draining lymph nodes (TDLNs) display distinct morphologic changes depending on the breast cancer subtype. For triple-negative breast cancers (TNBC), draining LNs display a higher amount of secondary lymphoid follicles, which can be regarded as a surrogate marker for an activated humoral immune response. In the present study, we focus on PD1+ T-follicular helper cells (Tfh) in TDLNs of TNBC, since PD1+ Tfh are drivers of the germinal center (GC) reaction. We quantified PD1+ Tfh in 22 sentinel LNs with 853 GCs and interfollicular areas from 19 patients with TNBC by morphometry from digitalized immunostained tissue sections. Overall survival was significantly worse for patients with a higher number and area density of PD1+ Tfh within GCs of TDLNs. Further, we performed T-cell receptor gamma chain (TRG) analysis from microdissected tissue in the primary tumor and TDLNs. Eleven patients showed the same TRG clones in the tumor and the LN. Five patients shared the same TRG clones in the tumor and the GCs. In two patients, those clones were highly enriched inside the GCs. Enrichment of identical TRG clones at the tumor site vs. the TDLN was associated with improved overall survival. TDLNs are important relays of cancer immunity and enable surrogate approaches to predict the outcome of TNBC itself.

SUBMITTER: Bronsert P

PROVIDER: S-EPMC7504397 | biostudies-literature | 2020 Aug

REPOSITORIES: biostudies-literature

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High Numbers and Densities of PD1+ T-Follicular Helper Cells in Triple-Negative Breast Cancer Draining Lymph Nodes Are Associated with Lower Survival.

Bronsert Peter P von Schoenfeld Anna A Villacorta Hidalgo Jose J Kraft Stefan S Pfeiffer Jens J Erbes Thalia T Werner Martin M Seidl Maximilian M

International journal of molecular sciences 20200819 17

Breast cancer tumor draining lymph nodes (TDLNs) display distinct morphologic changes depending on the breast cancer subtype. For triple-negative breast cancers (TNBC), draining LNs display a higher amount of secondary lymphoid follicles, which can be regarded as a surrogate marker for an activated humoral immune response. In the present study, we focus on PD1+ T-follicular helper cells (Tfh) in TDLNs of TNBC, since PD1+ Tfh are drivers of the germinal center (GC) reaction. ...[more]

PMID: 32824917

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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

High Numbers and Densities of PD1+ T-Follicular Helper Cells in Triple-Negative Breast Cancer Draining Lymph Nodes Are Associated with Lower Survival.

Publications

High Numbers and Densities of PD1<sup>+</sup> T-Follicular Helper Cells in Triple-Negative Breast Cancer Draining Lymph Nodes Are Associated with Lower Survival.

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