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

Background Immune 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 knowled...

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Bibliographic Details
Published in:Journal for immunotherapy of cancer Vol. 7; no. 1; pp. 133 - 14
Main Authors: van Pul, Kim M., Vuylsteke, Ronald J.C.L.M., van de Ven, Rieneke, te Velde, Elisabeth A., Rutgers, Emiel J. Th, van den Tol, Petrousjka M., Stockmann, Hein B.A.C., de Gruijl, Tanja D.
Format: Journal Article
Language:English
Published: London BioMed Central 22.05.2019
BioMed Central Ltd
BMJ Publishing Group LTD
BMJ Publishing Group
Subjects:
Adjuvant chemotherapy
Antigens
Breast cancer
Cancer
Cancer metastasis
Cancer treatment
Care and treatment
Chemotherapy
Clinical/Translational Cancer Immunotherapy
Dendritic cell
Dendritic cells
Flow cytometry
Genetic aspects
Hormones
Hospitals
Immune suppression
Immunology
Immunotherapy
Lymphatic system
Lymphocytes
Mastectomy
Medical prognosis
Medical research
Medicine
Medicine & Public Health
Metastasis
Oncology
Pathology
Research Article
Sentinel lymph node
Surgery
T cells
Tumor-infiltrating lymphocytes
Tumors
Immune suppression
Dendritic cell
Breast cancer
Sentinel lymph node
ISSN:2051-1426, 2051-1426
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Summary:Background Immune 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. Methods Viable 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. Results Our 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. Conclusion These 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.
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ISSN:2051-1426
2051-1426
DOI:10.1186/s40425-019-0605-1