Dual roles for immune metagenes in breast cancer prognosis and therapy prediction

Abstract

Background: Neoadjuvant chemotherapy for breast cancer leads to considerable variability in clinical responses, with only 10 to 20% of cases achieving complete pathologic responses (pCR). Biological and clinical factors that determine the extent of pCR are incompletely understood. Mounting evidence indicates that the patient's immune system contributes to tumor regression and can be modulated by therapies. The cell types most frequently observed with this association are effector tumor infiltrating lymphocytes (TILs), such as cytotoxic T cells, natural killer cells and B cells. We and others have shown that the relative abundance of TILs in breast cancer can be quantified by intratumoral transcript levels of coordinately expressed, immune cell-specific genes. Through expression microarray analysis, we recently discovered three immune gene signatures, or metagenes, that appear to reflect the relative abundance of distinct tumor-infiltrating leukocyte populations. The B/P (B cell/plasma cell), T/NK (T cell/natural killer cell) and M/D (monocyte/dendritic cell) immune metagenes were significantly associated with distant metastasis-free survival of patients with highly proliferative cancer of the basal-like, HER2-enriched and luminal B intrinsic subtypes. Methods: Given the histopathological evidence that TIL abundance is predictive of neoadjuvant treatment efficacy, we evaluated the therapy-predictive potential of the prognostic immune metagenes. We hypothesized that pre-chemotherapy immune gene signatures would be significantly predictive of tumor response. In a multi-institutional, meta-cohort analysis of 701 breast cancer patients receiving neoadjuvant chemotherapy, gene expression profiles of tumor biopsies were investigated by logistic regression to determine the existence of therapy-predictive interactions between the immune metagenes, tumor proliferative capacity, and intrinsic subtypes. Results: By univariate analysis, the B/P, T/NK and M/D metagenes were all significantly and positively associated with favorable pathologic responses. In multivariate analyses, proliferative capacity and intrinsic subtype altered the significance of the immune metagenes in different ways, with the M/D and B/P metagenes achieving the greatest overall significance after adjustment for other variables. Conclusions: Gene expression signatures of infiltrating immune cells carry both prognostic and therapy-predictive value that is impacted by tumor proliferative capacity and intrinsic subtype. Anti-tumor functions of plasma B cells and myeloid-derived antigen-presenting cells may explain more variability in pathologic response to neoadjuvant chemotherapy than previously recognized.

Prognostic and predictive value of NanoString-based immune-related gene signatures in a neoadjuvant setting of triple-negative breast cancer: relationship to tumor-infiltrating lymphocytes

“…The expression of immunoglobulin jC that is produced by plasma cells has been associated with the prognosis of patients with breast cancer [17]. A recent study revealed that B cells/plasma B cells (B/P) and monocytes/dendritic cells (M/D) metagenes provide the most robust therapypredictive performance among the immune metagenes [34]. The spatio-temporal dynamics of 28 different immune cell types infiltrating colorectal carcinomas were analyzed previously [35].…”

Tumour-Infiltrating Lymphocytes (TILs) in Breast Cancer: a Predictive or a Prognostic Marker?

“…Moreover, numerous studies have shown upregulation in FoxP3 + Tregs [69, 70•, 71] and MDSCs [45,[72][73][74] as well as elevated arginase [75,76], dampening immunity in breast cancer through suppressive actions on CTLs, DCs and NK cells [76,77]. Metabolic enzymes such as indoleamine 2,3-dioxygenase (IDO), which is expressed by tumour cells and MDSCs, can also inhibit immune responses though local depletion of amino acids which are essential for anabolic functions, particularly in T lymphocytes [78,79]. Immune checkpoint molecules have developed great interest and become important cancer immunology therapeutics in recent years [26,80].…”

microRNA as a systemic intervention in the specific breast cancer subtypes with C‐MYC impacts; introducing subtype‐based appraisal tool

“…regulating of cell cycle (Amati et al, 1998), cell proliferation (Facchini & Penn, 1998), DNA replication (Dang et al, 2006), chromatin structure (Grandori et al, 2000;Knoepfler et al, 2006), response to growth factors (Grandori et al, 2000), ribosome biogenesis (Dai & Lu, 2008), protein synthesis (Ruggero, 2009), cell adhesion and cytoskeleton, angiogenesis (Shchors & Evan, 2007), metabolic pathway (Shajahan-Haq et al, 2015;Shen et al, 2015), apoptosis (Meyer et al, 2006;Nilsson & Cleveland, 2003), cellular senescence (Nilsson & Cleveland, 2003), immune activation as well as immunosuppression at the expense of cell survival capacity of tumor mass (Alistar et al, 2014;Jézéquel et al, 2015;Robbins & Morelli, 2014;Teschendorff et al, 2010). In other words, it is important to indicate that C-MYC should mostly cooperate with so many other oncogenic factors, namely, other oncoproteins and miRNAs to augment incidence and multiplicity of the mentioned processes.…”

“…In principle, miRNAs are implicated in various biological processes including cell growth, development, differentiation, proliferation, and apoptosis (PCD: programed cell dead), that the underlying molecular mechanisms can be modulated by different oncogenic and tumor suppressive miRNAs in various directions (Enerly et al, 2011;Hayes et al, 2014;Hwang & Mendell, 2006;Iorio & Croce, 2012a;Kaboli et al, 2015;Leung & Sharp, 2010;Van der Auwera et al, 2010). Furthermore, it is important to note that the imbalance miRNA expression can emerge along with other factors to rewire feasible molecular background despite the physical conditions and the breast cancer patients' immune system activity, either directly or indirectly (Alistar et al, 2014). In this respect, one undeniable point is that some miRNAs can present in two paradoxical routes, including tumor suppressive state and oncogenic form that are called tumor suppressor miRNAs and oncogenic miRNAs, respectively.…”