Tumor specific regulatory T cells in the bone marrow of breast cancer patients selectively upregulate the emigration receptor S1P1

Anchana Rathinasamy,Christel Herold-Mende,Philipp Beckhove,Christoph Domschke,Markus H Gräler,Ludmila Umansky,Steffen Dettling,David Jansen,Florian Schuetz,Yingzi Ge,Jennifer Hartmann,Felix Lasitschka,Hans-Henning Böhm

doi:10.1007/s00262-017-1964-4

Abstract

Regulatory T cells (Treg) hamper anti-tumor T-cell responses resulting in reduced survival and failure of cancer immunotherapy. Among lymphoid organs, the bone marrow (BM) is a major site of Treg residence and recirculation. However, the process governing the emigration of Treg from BM into the circulation remains elusive. We here show that breast cancer patients harbour reduced Treg frequencies in the BM as compared to healthy individuals or the blood. This was particularly the case for tumor antigen-specific Treg which were quantified by MHCII tumor peptide loaded tetramers. We further demonstrate that decreased Treg distribution in the BM correlated with increased Treg redistribution to tumor tissue, suggesting that TCR triggering induces a translocation of Treg from the BM into tumor tissue. Sphingosine-1-phosphate receptor 1 (S1P1)—which is known to mediate exit of immune cells from lymphoid organs was selectively expressed by tumor antigen-specific BM Treg. S1P1 expression could be induced in Treg by BM-resident antigen-presenting cells (BMAPCs) in conjunction with TCR stimulation, but not by TCR stimulation or BMAPCs alone and triggered the migration of Treg but not conventional T cells (Tcon) to its ligand Sphingosine-1-phosphate (S1P). Interestingly, we detected marked S1P gradients between PB and BM in breast cancer patients but not in healthy individuals. Taken together, our data suggest a role for S1P1 in mediating the selective mobilization of tumor specific Treg from the BM of breast cancer patients and their translocation into tumor tissue.

Highlights

Treg are a subset of CD4+ T cells that maintain self tolerance by exerting a plethora of immune suppressive activities on various immune cells—most prominently autoreactive T effector cells
Infiltration of Treg into tumors is associated with enhanced tumor growth and poor prognosis [1,2,3] and their therapeutic depletion through antibody-dependent cell-mediated cytotoxicity (ADCC)-proficient antibodies against a Treg-associated molecule CTLA-4 or low-dose cyclophosphamide treatment can improve anti-tumor T-cell responses and overall survival of patients [4, 5]
Our findings suggest that upregulation of Sphingosine-1-phosphate receptor 1 (S1P1) on tumor antigen-specific Treg mediates their preferential exit from the bone marrow (BM)

Summary

Introduction

Treg are a subset of CD4+ T cells that maintain self tolerance by exerting a plethora of immune suppressive activities on various immune cells—most prominently autoreactive T effector cells. Treg play a detrimental role in anti-tumor T-cell responses in cancer patients. Data available until date clearly demonstrate the prognostic relevance of tumor infiltrating Treg [7]. This is the case in breast cancer. Many breast cancer patients develop tumor antigen-specific effector T-cell responses [8,9,10,11,12], and tumor specific Treg [13]. Treg accumulation in breast tumors is associated with poor overall and relapse free survival and used as an independent prognostic factor in predicting patients at high risk of relapse [14]

Methods

Results

Conclusion