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

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Abstract

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.

Electronic supplementary material

The online version of this article (10.1186/s40425-019-0605-1) contains supplementary material, which is available to authorized users.

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Immune-regulated pathways influence multiple aspects of cancer development. In this article we demonstrate that both macrophage abundance and T-cell abundance in breast cancer represent prognostic indicators for recurrence-free and overall survival. We provide evidence that response to chemotherapy is in part regulated by these leukocytes; cytotoxic therapies induce mammary epithelial cells to produce monocyte/macrophage recruitment factors, including colony stimulating factor 1 (CSF1) and interleukin-34, which together enhance CSF1 receptor (CSF1R)-dependent macrophage infiltration. Blockade of macrophage recruitment with CSF1R-signaling antagonists, in combination with paclitaxel, improved survival of mammary tumor-bearing mice by slowing primary tumor development and reducing pulmonary metastasis. These improved aspects of mammary carcinogenesis were accompanied by decreased vessel density and appearance of antitumor immune programs fostering tumor suppression in a CD8+ T-cell-dependent manner. These data provide a rationale for targeting macrophage recruitment/response pathways, notably CSF1R, in combination with cytotoxic therapy, and identification of a breast cancer population likely to benefit from this novel therapeutic approach. These findings reveal that response to chemotherapy is in part regulated by the tumor immune microenvironment and that common cytotoxic drugs induce neoplastic cells to produce monocyte/macrophage recruitment factors, which in turn enhance macrophage infiltration into mammary adenocarcinomas. Blockade of pathways mediating macrophage recruitment, in combination with chemotherapy, significantly decreases primary tumor progression, reduces metastasis, and improves survival by CD8+ T-cell-dependent mechanisms, thus indicating that the immune microenvironment of tumors can be reprogrammed to instead foster antitumor immunity and improve response to cytotoxic therapy.

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Is Open Access

Superior antigen cross-presentation and XCR1 expression define human CD11c+CD141+ cells as homologues of mouse CD8+ dendritic cells

Annabell Bachem, Steffen Güttler, Evelyn Hartung … (2010)

In recent years, human dendritic cells (DCs) could be subdivided into CD304+ plasmacytoid DCs (pDCs) and conventional DCs (cDCs), the latter encompassing the CD1c+, CD16+, and CD141+ DC subsets. To date, the low frequency of these DCs in human blood has essentially prevented functional studies defining their specific contribution to antigen presentation. We have established a protocol for an effective isolation of pDC and cDC subsets to high purity. Using this approach, we show that CD141+ DCs are the only cells in human blood that express the chemokine receptor XCR1 and respond to the specific ligand XCL1 by Ca2+ mobilization and potent chemotaxis. More importantly, we demonstrate that CD141+ DCs excel in cross-presentation of soluble or cell-associated antigen to CD8+ T cells when directly compared with CD1c+ DCs, CD16+ DCs, and pDCs from the same donors. Both in their functional XCR1 expression and their effective processing and presentation of exogenous antigen in the context of major histocompatibility complex class I, human CD141+ DCs correspond to mouse CD8+ DCs, a subset known for superior antigen cross-presentation in vivo. These data define CD141+ DCs as professional antigen cross-presenting DCs in the human.

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Author and article information

Contributors

Kim M. van Pul: kvanpul@gmail.com

Ronald J.C.L.M. Vuylsteke: vuylsteke@spaarnegasthuis.nl

Rieneke van de Ven: r.vandeven@vumc.nl

Elisabeth A. te Velde: e.tevelde@adrz.nl

Emiel J. Th. Rutgers: e.rutgers@nki.nl

Petrousjka M. van den Tol: MP.vandentol@vumc.nl

Hein B.A.C. Stockmann: stockmann@spaarnegasthuis.nl

Tanja D. de Gruijl:

ORCID: http://orcid.org/0000-0003-1464-8978

+31204444063 , td.degruijl@vumc.nl

Journal

Journal ID (nlm-ta): J Immunother Cancer

Journal ID (iso-abbrev): J Immunother Cancer

Title: Journal for Immunotherapy of Cancer

Publisher: BioMed Central (London )

ISSN (Electronic): 2051-1426

Publication date (Electronic): 22 May 2019

Publication date PMC-release: 22 May 2019

Publication date Collection: 2019

Volume: 7

Electronic Location Identifier: 133

Affiliations

[1 ]ISNI 0000 0004 1754 9227, GRID 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

[2 ]ISNI 0000 0004 0568 6419, GRID grid.416219.9, Department of Surgery, , Spaarne Gasthuis, ; Boerhaavelaan 22, 2035 RC Haarlem, The Netherlands

[3 ]ISNI 0000 0004 1754 9227, GRID 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

[4 ]ISNI 0000 0004 1754 9227, GRID grid.12380.38, Department of Surgical Oncology, Amsterdam UMC, , Vrije Universiteit Amsterdam, Cancer Center Amsterdam, ; De Boelelaan 1117, 1081 HV Amsterdam, The Netherlands

[5 ]GRID grid.430814.a, Department of Surgery, , The Netherlands Cancer Institute, ; Plesmanlaan 121, 1066 CX Amsterdam, The Netherlands

Author information

Tanja D. de Gruijl http://orcid.org/0000-0003-1464-8978

Article

Publisher ID: 605

DOI: 10.1186/s40425-019-0605-1

PMC ID: 6530094

PubMed ID: 31118093

SO-VID: c7aa1898-8556-4da5-aec4-875a680be00c

License:

Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License ( http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver ( http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.

History

Date received : 2 November 2018

Date accepted : 26 April 2019

Funding

Funded by: FundRef http://dx.doi.org/10.13039/501100008382, Stichting A Sister's Hope;

Funded by: FundRef http://dx.doi.org/10.13039/501100004622, KWF Kankerbestrijding;

Award ID: KWF VU2015-7864

Award Recipient : Rieneke van de Ven

Custom metadata

Keywords: dendritic cell,sentinel lymph node,immune suppression,breast cancer

Data availability:

Keywords: dendritic cell, sentinel lymph node, immune suppression, breast cancer