Profile of Immune Cells in Axillary Lymph Nodes Predicts Disease-Free Survival in Breast Cancer

Abstract

BackgroundWhile lymph node metastasis is among the strongest predictors of disease-free and overall survival for patients with breast cancer, the immunological nature of tumor-draining lymph nodes is often ignored, and may provide additional prognostic information on clinical outcome.Methods and FindingsWe performed immunohistochemical analysis of 47 sentinel and 104 axillary (nonsentinel) nodes from 77 breast cancer patients with 5 y of follow-up to determine if alterations in CD4, CD8, and CD1a cell populations predict nodal metastasis or disease-free survival. Sentinel and axillary node CD4 and CD8 T cells were decreased in breast cancer patients compared to control nodes. CD1a dendritic cells were also diminished in sentinel and tumor-involved axillary nodes, but increased in tumor-free axillary nodes. Axillary node, but not sentinel node, CD4 T cell and dendritic cell populations were highly correlated with disease-free survival, independent of axillary metastasis. Immune profiling of ALN from a test set of 48 patients, applying CD4 T cell and CD1a dendritic cell population thresholds of CD4 ≥ 7.0% and CD1a ≥ 0.6%, determined from analysis of a learning set of 29 patients, provided significant risk stratification into favorable and unfavorable prognostic groups superior to clinicopathologic characteristics including tumor size, extent or size of nodal metastasis (CD4, p < 0.001 and CD1a, p < 0.001). Moreover, axillary node CD4 T cell and CD1a dendritic cell populations allowed more significant stratification of disease-free survival of patients with T1 (primary tumor size 2 cm or less) and T2 (5 cm or larger) tumors than all other patient characteristics. Finally, sentinel node immune profiles correlated primarily with the presence of infiltrating tumor cells, while axillary node immune profiles appeared largely independent of nodal metastases, raising the possibility that, within axillary lymph nodes, immune profile changes and nodal metastases represent independent processes.ConclusionThese findings demonstrate that the immune profile of tumor-draining lymph nodes is of novel biologic and clinical importance for patients with early stage breast cancer.

Regional immunity in melanoma: immunosuppressive changes precede nodal metastasis

“…8 Similar to another group, 9 we also did not detect any differences in Foxp3 þ cells between sentinel lymph nodes groups. Unlike our findings, two other groups have reported increases in Foxp3 þ cells in melanoma-involved lymph nodes compared with those without metastasis, 10,11 which is similar to results reported in breast cancer.…”

The biology of personalized cancer medicine: Facing individual complexities underlying hallmark capabilities

“…On the other hand, the relative abundance of immunosuppressive T‐regulatory cells (Tregs) (Bates et al., 2006; Pages et al., 2010) or CD4 + effector T‐cells (Denardo et al., 2011; Kohrt et al., 2005; Zhou et al., 2009) can be prognostic of comparatively poor outcome, as can the abundance of various myeloid cell types, including macrophages, neutrophils and immature myeloid cells (Qian and Pollard, 2010; Steidl et al., 2011; Zhou et al., 2009), a subset of which are referred to as myeloid‐derived suppressor cells on account of their ability to inhibit T‐cell functions (Sica and Bronte, 2007). Furthermore, studies in mouse models of cancer have revealed that profuse myeloid cell infiltration correlates with resistance to antiangiogenic therapies targeting the VEGF‐signaling axis (Bergers and Hanahan, 2008; Ferrara, 2010; Squadrito and De Palma, 2011), or accelerated tumor re‐growth following local tumor irradiation (Ahn and Brown, 2008; Kioi et al., 2010; Kozin et al., 2010).…”

Leukocytes in Mammary Development and Cancer

“…High percentages of CD4 þ T cells in primary breast cancers positively correlate with markers of disease progression, including metastatic spread to sentinel lymph nodes and increased primary tumor size (Chin et al 1992;Kohrt et al 2005). The extent of T-cell infiltration into invasive breast carcinomas has been reported to range from 1% -45% of the total cellular mass (Chin et al 1992).…”

“…However, the exact composition of T-lymphocyte infiltration varies greatly and may profoundly affect disease progression and overall patient survival. Perhaps more significant, the ratio of CD4 þ to CD8 þ T cells or T H 2 to T H 1 cells present in primary tumors, where CD4 þ or T H 2 cells are more frequent than CD8 þ or T H 1 cells, correlates with lymph node metastasis and reduced overall patient survival (Chin et al 1992;Kohrt et al 2005). More recently, unsupervised expression profiling from breast cancer-associated stroma revealed a gene signature predictive of good prognostic outcome (.98%, 5-year survival) that was functionally enriched for elements of a T H 1-type immune response, including genes suggestive of cytotoxic T lymphocyte (CTL) and natural killer (NK) cell activity (Finak et al 2008).…”

“…Conversely, high levels of FOXP3 þ T reg cells predict diminished relapsefree and overall patient survival (Bates et al 2006(Bates et al , 2007. Although it is unclear if presence of CD8 þ CTLs alone provides any prognostic information for breast cancer, the presence of high percentages of CD4 þ T helper cells at primary tumor sites positively correlates with disease progression, e.g., metastatic spread to sentinel lymph node (LN) and primary tumor size (Chin et al 1992;Kohrt et al 2005). The interpretation based on these clinical studies is that the type of CD4 þ effector T-cell response elicited in an emergent breast cancer may in part determine malignant and metastatic potential.…”