Abstract
Triple negative breast cancer (TNBC) is an aggressive subtype with limited therapeutic options. New opportunities are emerging from current comprehensive characterization of tumor immune infiltration and fitness. Therefore, effectiveness of current chemotherapies and novel immunotherapies are partially dictated by host inflammatory and immune profiles. However, further progress in breast cancer immuno-oncology is required to reach a detailed awareness of the immune infiltrate landscape and to determine additional reliable and easily detectable biomarkers. In this study, by analyzing gene expression profiles of 54 TNBC cases we identified three TNBC clusters displaying unique immune features. Deep molecular characterization of immune cells cytolytic-activity and tumor-inflammation status reveled variability in the local composition of the immune infiltrate in the TNBC clusters, reconciled by tumor-infiltrating lymphocytes counts. Platelet-to-lymphocyte ratio (PLR), a blood systemic parameter of inflammation evaluated using pre-surgical blood test data, resulted negatively correlated with local tumoral cytolytic activity and T cell–inflamed microenvironment, whereas tumor aggressiveness score signature positively correlated with PLR values. These data highlighted that systemic inflammation parameters may represent reliable and informative markers of the local immune tumor microenvironment in TNBC patients and could be exploited to decipher tumor infiltrate properties and consequently to select the most appropriate therapies.
Highlights
Triple negative breast cancer (TNBC) represents a minority (10–17%) of all breast carcinomas (BC) [1], it stands for an important challenge in actual clinical practice due to the poor clinical outcomes compared with non-TNBC [2,3]
Immunophenogram of immune-active subtype (ImA) presents an enrichment in tumor immune-intrinsic factors, such as immunoinhibitors and major histocompatibility complex class molecules (e.g., HLA, TAP1), as well as an enhancement in effector cells (e.g., activated CD8 T cells (CD8+) and activated memory CD4 T cells (CD4+)), which results in a immunophenoscore of 10
We described the role of platelet-derived growth factor receptors beta (PDGFRβ) in mediating the endothelial differentiation of triple negative breast carcinoma cells [72] and we recently described the involvement of PDGFRβ in the regulation of the CDCP1 [73], a transmembrane protein which is overexpressed in TNBCs and is involved in tumor progression [74]
Summary
Triple negative breast cancer (TNBC) represents a minority (10–17%) of all breast carcinomas (BC) [1], it stands for an important challenge in actual clinical practice due to the poor clinical outcomes compared with non-TNBC [2,3]. Growing evidence shows a highly diverse immunogenic activity across breast cancer subtypes that may be correlated with phenotypic heterogeneity of breast cancer [4,5,6,7]. TNBC is associated with high density of tumor infiltrating lymphocytes (TILs) defined by histopathology evaluation, which represents a robust intratumoral inflammatory response describing triple negative (TN) tumors as an immunogenic neoplasia [4,5,6]. Diverse evidence indicated that tumor-associated inflammatory cells improve survival in BC, including TNBC [4,7,13,14]. An enhanced innate and adaptive immunity, as revealed by TILs count, improves chemotherapy [14,15] and radiotherapy responses, regardless of breast cancer subtype [16]
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