Composite analysis of immunological and metabolic markers defines novel subtypes of triple negative breast cancer

Abstract

Cancer biology is influenced by the tumor microenvironment that impacts on disease prognosis and therapeutic intervention. The inter-relationship of tumor infiltrating lymphocytes, immune response regulators, and a glycolytic tumor environment was evaluated in a cohort of 183 largely consecutive patients with triple negative breast cancer diagnosis. High levels of tumor infiltrating lymphocytes were associated with improved survival of triple negative breast cancer cases. However, elevated levels of PD-L1, CD163, and FOXP3 were individually associated with significantly decreased overall survival. These three determinants were significantly correlated, and could serve to differentiate the prognostic significance of tumor infiltrating lymphocytes. Interestingly, a glycolytic tumor environment, as determined by the expression of MCT4 in the tumor stroma, was associated with the immune evasive environment and poor prognosis. Clustering of all markers defined four distinct triple negative breast cancer subtypes that harbored prognostic significance in multi-variate analysis. Immune and metabolic markers stratify triple negative breast cancer into subtypes that have prognostic significance and implications for therapies targeting immune checkpoints and tumor metabolism.

Assessment of outcomes and novel immune biomarkers in metaplastic breast cancer: a single institution retrospective study

“…Magnification: × 100 [34]. Finally, the levels of immune marker staining seen in our MBC samples (lower CD8, higher CD163, and higher PD-L1) is comparable to data from previous publications using TNBC samples [25,28]. The prognosis of MBC, when compared to TNBC, has traditionally been known to be worse, but survival outcomes have varied across numerous studies.…”

“…Figure 3 shows images of the different immune markers and PD-L1 expressions in two metaplastic breast carcinomas. The immune marker profile of our MBC samples is analogous to those generated from TNBC samples in previous studies, which demonstrated associations between lower CD8, higher CD163, higher PD-L1 staining and worse prognosis [25,28].…”

“…CD163, a scavenger receptor for the hemoglobin-haptoglobin complex, is a marker for alternatively activated (M2) polarized macrophages [26]. CD163 + tumor-associated macrophage (TAM) infiltration in tumor stroma is also of clinical interest as it is strongly associated with TNBC and is associated with poorer survival in TNBC with low TIL levels [27][28][29], though the role of CD163 + TAM infiltration in MBC has not been examined.…”

Programmed Cell Death Ligand 1 in Breast Cancer: Technical Aspects, Prognostic Implications, and Predictive Value

“…PD‐L1 expression evaluated by IHC on untreated primary BC has been associated with both better and poorer clinical outcome. In particular, several authors reported poorer disease‐free survival (DFS)/recurrence‐free survival (RFS) and/or overall survival (OS) in cases of higher PD‐L1 expression on primary BC , especially in the TN subtype . These results seems to be consistent with the previously mentioned correlation between PD‐L1 expression and unfavorable clinicopathological BC features, thus possibly indicating that PD‐L1 expression may be part of the immune evasion process taking place in the context of tumor microenvironment .…”

Downregulation of MCT4 for lactate exchange promotes the cytotoxicity of NK cells in breast carcinoma

“…Monocarboxylic acid transporter 4 (SLC16A3/MCT4) is one of the membrane protein stubs in cells that is structurally able to output lactic and pyruvic acids and affect the acidity of the tumor microenvironments. [15][16][17] High expression of MCT4 has been reported to be a biomarker in various types of tumors, [18][19][20][21][22][23][24] which makes it an appealing therapeutic target in cancers. The blockade of MCT4 expression has been shown to represent a novel treatment target in glioblastoma, large B-cell lymphoma, and multiple myeloma.…”