Abstract
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.
Highlights
Immune regulated pathways influence both breast cancer (BrC) development and response to adjuvant chemotherapy
Our data show that BrC-induced immune suppression in tumor-involved sentinel lymph node (SLN), as evidenced by increased Regulatory T-Cells (Treg) and myeloid derived suppressor cells (MDSC) rates as well as by a generalized state of effector T cell suppression, coincides with hampered activation of LN-resident conventional Dendritic cells (DC) (cDC) and plasmacytoid DC subsets rather than migratory DC subsets
We did detect CD1a−CD11c+CD14+ LNR-cDC in healthy lymph nodes (HLN) (0.12%), frequencies in the BrC SLN samples were so low (< 0.04% for both metastasis positive and negative SLN, both significantly lower compared to HLN (p < 0.0001)) that reliable gating for subsequent marker analysis did not prove possible
Summary
Immune regulated pathways influence both breast cancer (BrC) development and response to (neo) adjuvant chemotherapy. The clinical relevance of BrC immunogenicity has recently been confirmed by multiple studies showing that prevalence of tumor infiltrating lymphocytes (TIL) is associated with a favourable prognosis and higher pathologic complete response rates to (neo)adjuvant chemotherapy, in Triple Negative and HER2+ breast cancers [8, 9]. These favourable anti-tumor conditions at the primary tumor site are a result of antitumor responses generated in the regional tumor-draining lymph nodes (TDLN). Tumor-derived factors can inhibit differentiation and activation of DC and instead promote the development of immunosuppressive macrophages and myeloid derived suppressor cells (MDSC) that in turn can expand regulatory T cells (Treg), all of which interfere with cytotoxic T cell functionality and contribute to tumor progression and spread [10,11,12]
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