Altered local and systemic immune profiles underlie lymph node metastasis in breast cancer patients

Abstract

Cancer-mediated immune dysfunction contributes to tumor progression and correlates with patient outcome. Metastasis to tumor draining lymph nodes (TDLNs) is an important step in breast cancer progression and is used to predict patient outcome and survival. While lymph nodes are important immune organs, the role of immune cells in TDLNs has not been thoroughly investigated. We hypothesized that the host immune response in node negative (NN) patients is more intact and thereby can resist tumor invasion compared to node positive (NP) patients. As such, lymph node metastasis requires breakdown of the host immune response in addition to escape of cancer cells from the tumor. To investigate the immunological differences between NN and NP breast cancer patients, we purified and profiled immune cells from the three major compartments where cancer and immune cells interact: tumor, TDLNs, and peripheral blood. Significant down-regulation of genes associated with immune-related pathways and up-regulation of genes associated with tumor-promoting pathways was consistently observed in NP patients’ TDLNs compared to NN patients. Importantly, these signatures were seen even in NP patients’ tumor-free TDLNs, suggesting that such immune changes are not driven solely by local tumor invasion. Furthermore, similar patterns were also observed in NP patients’ tumor and blood immune cells, suggesting that immunological differences between NN and NP patients are systemic. Together, these findings suggest that alterations in overall immune function may underlie risk for LN metastasis in breast cancer patients.

Lymphatic vessel density is associated with CD8+ T cell infiltration and immunosuppressive factors in human melanoma

“…examined differences in immune cell signatures between tumor-free LNs of node negative breast cancer patients and tumor-invaded sentinel lymph nodes (SLNs), tumor-free SLNs or tumor-free non-sentinel lymph nodes (NSLNs) of node positive breast cancer patients. 65 This study provided the first evidence of altered immune regulation depending on whether neighboring LNs were metastatic or not. We investigated the immunological differences between tumor-free LNs from patients with positive versus negative LN dissections.…”

Transcriptional Profiling of Melanoma Sentinel Nodes Identify Patients with Poor Outcome and Reveal an Association of CD30+ T Lymphocytes with Progression

“…Hence, the SN represents a key component of the tumor microenvironment that potentially promotes immune tolerance. Increasing evidence supports the view that the triggering of immunosuppressive pathways at the microenvironment level, which inactivate tumor-specific T-cell responses, is associated with systemic immune dysfunction (4). These signs of local and systemic immunologic dysfunction, including the accumulation of myeloid-derived suppressor cells (5), tumor-specific CTLs with an anergic phenotype (6), regulatory T cells (Treg) and Th2 cells (7,8), and dendritic cells (DC) with diminished functionality (9), are definitively detected in those patients with a poor clinical outcome (10,11).…”

Immune response markers in sentinel nodes may predict melanoma progression

“…Immunological defects affecting various immune cell components have been extensively documented in SN of melanoma and breast carcinoma patients. Decreased frequencies of CD8 + effector T cells and stimulatory CD86 + and CD11c + dendritic cells, as well as the accumulation of Foxp3 + regulatory T cells (Tregs) and T helper 2 (Th2) cytokines, have been reported in SN relative to immune cell frequency and composition in non-tumor draining nodes 1 - 3 . This altered immune phenotype, possibly permitting, or even promoting, the development of further cancer metastases, supports the premise that the SN is a key component of the tumor microenvironment and a sensor of systemic immune dysfunctions, potentially heralding poor outcome.…”