Selectively hampered activation of lymph node-resident dendritic cells precedes profound T cell suppression and metastatic spread in the breast cancer sentinel lymph node

Journal for ImmunoTherapy of Cancer

Ronald J.C.L.M. Vuylsteke¹  Hein B.A.C. Stockmann¹  Tanja D. de Gruijl²  Rieneke van de Ven²  Elisabeth A. te Velde³  Petrousjka M. van den Tol³  Kim M. van Pul⁴  Emiel J. Th. Rutgers⁵ 

[1] 0000 0004 0568 6419, grid.416219.9, Department of Surgery, Spaarne Gasthuis, Boerhaavelaan 22, 2035 RC, Haarlem, The Netherlands;0000 0004 1754 9227, grid.12380.38, Department of Medical Oncology, Amsterdam University Medical Center, Vrije Universiteit Amsterdam, Cancer Center Amsterdam, De Boelelaan 1117, 1081 HV, Amsterdam, The Netherlands;0000 0004 1754 9227, grid.12380.38, Department of Surgical Oncology, Amsterdam UMC, Vrije Universiteit Amsterdam, Cancer Center Amsterdam, De Boelelaan 1117, 1081 HV, Amsterdam, The Netherlands;0000 0004 1754 9227, grid.12380.38, Departments of Medical and Surgical Oncology, Amsterdam UMC, Vrije Universiteit Amsterdam, Cancer Center Amsterdam, De Boelelaan 1117, 1081 HV, Amsterdam, The Netherlands;grid.430814.a, Department of Surgery, The Netherlands Cancer Institute, Plesmanlaan 121, 1066 CX, Amsterdam, The Netherlands;

关键词: Dendritic cell;    Sentinel lymph node;    Immune suppression;    Breast cancer;   

DOI  :  10.1186/s40425-019-0605-1

来源: publisher

【 摘 要 】

BackgroundImmune regulated pathways influence both breast cancer (BrC) development and response to (neo)adjuvant chemotherapy. The sentinel lymph node (SLN), as the first metastatic site, is also the first site where BrC-induced suppression of immune effector subsets occurs. Since intricate knowledge of the phenotypic and functional status of these immune effector subsets is lacking, we set out to map the immune landscape of BrC SLN.MethodsViable LN cells from BrC SLN (n = 58) were used for detailed flowcytometry-assisted mapping of the immune landscape of BrC SLN in a comparative analysis with healthy (i.e. prophylactic mastectomy-derived) axillary lymph nodes (HLN, n = 17). Findings were related to clinicopathological characteristics.ResultsOur data show that BrC-induced immune suppression in tumor-involved SLN, as evidenced by increased Treg and MDSC rates as well as by a generalized state of T cell anergy, coincides with hampered activation of LN-resident (LNR) dendritic cell (DC) subsets rather than of migratory DC subsets. Importantly, suppression of these LN-resident DC subsets preceded profoundly disabled T cell effector functions in tumor-involved SLN. Furthermore, we provide evidence that the suppressed state of LNR-cDC is not only related to nodal involvement but is also related to high-risk breast cancer subtypes that lack expression of hormone receptors and may be a negative predictor of disease-free survival.ConclusionThese data thus provide new insights in the mechanisms underlying loco-regional immune suppression induced by BrC and how these relate to clinical outcome. They identify the LNR-cDC subset as a pivotal regulatory node in cellular immune suppressive pathways and therefore as a promising therapeutic target to combat immune suppression and secure the induction of effective antitumor immunity, e.g. in combination with neo-adjuvant chemotherapy. 

【 授权许可】

CC BY