Differential tumor infiltration by T-cells characterizes intrinsic molecular subtypes in breast cancer

Abstract

BackgroundMolecular subtypes of breast cancer and presence of tumor-infiltrating immune cells have both been implicated as important predictive and prognostic factors for improved risk stratification and treatment individualization of breast cancer patients. Their association, however, has not been studied in detail. The aim of this study was to evaluate the expression of the T cell markers CD8, FoxP3, CD3 and ζ-chain in molecular subtypes of the invasive margin and tumor center of breast cancer and corresponding sentinel nodes and to deduct prognostic information from these findings.MethodsTumor and sentinel node sections from 177 patients with primary, invasive, unilateral early-stage breast cancer were stained by immunohistochemistry and T-cell phenotypes quantified manually. Clinical data were collected from medical records.ResultsThe degree of T-cell infiltration and expression of all markers differed significantly among the molecular subtypes, being highest in non-luminal, more aggressive tumors: more T-cell infiltration and higher expression of all markers were associated with hormone receptor negativity, higher proliferation and higher histological grades, but also with larger tumor size. Basal-like tumors, and most remarkably their tumor centers, hosted the highest number of FoxP3+ T-cells with an unfavorable ratio to cytotoxic CD8+ T-cells. T-cell infiltration was generally higher in the invasive margin than the tumor center. A scoring system based on densities of CD3 and CD8 could significantly separate molecular subtypes (p < 0.001).ConclusionsThus, immunological patterns with functional implications within each subtype are associated with prognostic factors. These findings should be further validated in studies using larger patient populations and longer follow-up.Electronic supplementary materialThe online version of this article (doi:10.1186/s12967-016-0983-9) contains supplementary material, which is available to authorized users.

CDDO-Me Alters the Tumor Microenvironment in Estrogen Receptor Negative Breast Cancer

“…3a). Notably in human breast cancer, higher baseline proportion of all CD3 + populations is associated with subtypes with a poor prognosis and hormone receptor negativity 29 . While the proportion of CD3 + cells that were CD4 + did not change, the percentage of CD3 + cells that were positive for the cytotoxic T cell marker CD8 significantly increased, which is a positive prognostic indicator in human disease 10 .…”

Discovering lncRNA Mediated Sponge Interactions in Breast Cancer Molecular Subtypes

“…Interestingly, interferon alpha/beta signaling pathway is among the top pathways for Basal subtype (p-value 7.20 × 10 −23 ) while it is not found enriched in other subtypes (p-value cut-off 0.05 and FDR cutoff 1 × 10 −4 ). Considering the key role of interferon signaling in the immune system, and the positive correlation between immune cell infiltration and aggressiveness of Basal subtype of breast cancer, our results suggest that mRNAs involved in ceRNA interactions might contribute to the different immune profile of the Basal subtype [38,39]. Complement cascade induces cell proliferation which causes carcinogenesis including invasion, cell death, and metastasis [40], which are Basal subtype characteristics.…”

Biological Features of Lyuminal В Breast Cancer

“…В настоящее время повышен интерес онкологов к экс-прессии андрогеновых рецепторов (АR) на клетках рака молочной железы [11]. По данным различных авторов, AR встречаются на опухолевых клетках в 10-90% всех случаев РМЖ и относятся к наиболее часто экспрессиру-емым ядерным рецепторам [30,31,32]. В исследовании 2010 года Castellano et al рассматривалось два подтипа РМЖ: люминальный В (HER+) и люминальный В (HER-) в зависимости от экспрессии рецепторов к андрогенам.…”

“…Так, люминальные подтипы демонстрируют большую плот-ность всех субпопуляций лимфоцитов в центре опухоли, но меньшую по её краям, по сравнению с нелюминальны-ми подтипами. По данным проведенных исследований, иммунный ответ на люминальные подтипы оказался слабее, чем на нелю-минальные [30]. Одно из таких направлений -Т-клеточная терапия, ос-нованная на заборе Т-клеток пациента, обогащении их специфическими опухолевыми антигенами, стимуляции интерлейкином-2 и реинфузии пациенту.…”