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

Peter Bronsert,Thalia Erbes,Jens Pfeiffer,Anna Von Schoenfeld,Maximilian Seidl,Jose Villacorta Hidalgo,Stefan Kraft,Martin Werner

doi:10.3390/ijms21175948

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.

Highlights

Breast cancer prognosis has improved dramatically in recent years due to targeted therapeutic options
22 analyzed tumor draining LNs displayed 853 germinal center (GC), which were analyzed for area, roundness, and cellular composition of Bcl6+ PD1+ T-follicular helper cells (Tfh)
CD8+ cytotoxic T-cells were quantified in GCs and interfollicular areas

Summary

Introduction

Breast cancer prognosis has improved dramatically in recent years due to targeted therapeutic options. Triple-negative breast cancer (TNBC) is associated with poor patient overall survival. Tumor immunology is presently in the focus of therapeutic cancer research, for breast cancer. PD-1/PD-L1 checkpoint inhibitors “revive” T-cells (”exhausted” cytotoxic T-cells) within the tumor microenvironment by blocking the PD-1/PD-L1 interaction, which tumors use to inhibit a T-cell mediated immune response. As predictive surrogate markers for immune checkpoint inhibitor therapy, T-cell infiltration, tumor PD-L1 expression, and tumor mutational load are used [4,5]. Besides local intra- and peritumoral factors, systemic surrogate markers, such as PD-L1 expressing eosinophils and lymphocytes within the peripheral blood may be useful [6,7]

Methods

Results

Conclusion