Finally, this work suggests that gene expression detected by PCR or protein expression detected by immunohistochemistry using a commercially available antibody could serve as a robust immunologic biomarker

Finally, this work suggests that gene expression detected by PCR or protein expression detected by immunohistochemistry using a commercially available antibody could serve as a robust immunologic biomarker. In addition to their role in promoting antibody responses discussed above, JTE-952 B cells, which can function as antigen-presenting cells, may also have a role in inducing CD8+ and CD4+ T-cell responses that can help control tumor growth and metastasis [66]. system therefore plays a critical role in carcinogenesis. Recognizing this, in the 2011 update of the Hallmarks of cancer, Hanahan and Weinberg included evading immune destruction as a new hallmark and identified inflammation as an enabling characteristic for the acquisition of this and other hallmark JTE-952 capabilities [3]. Although breast cancer has not traditionally been considered to be an immunogenic tumor, recent molecular profiling data showed that all breast cancers have an inflammatory gene signature [4]. That same study demonstrated that immune signatures may be prognostic, with a gene signature favoring a high CD8+ cytotoxic T lymphocyte (CTL) and CD4+ T helper (Th) type 1 response being a strong predictor of good outcome relative to a predominant Th type 2 response. In addition, there are data showing that the presence of tumor-infiltrating lymphocytes (TILs) or the high expression of immune gene signatures may predict response to therapy [5,6]. Therefore, there is growing interest in characterizing the immune aspects of the breast tumor microenvironment. In this review, we will discuss the available data regarding the immune response within the breast tumor microenvironment, highlighting studies that have shown that the immune response has predictive or prognostic significance. Prognostic impact of intratumoral immune response Pathologic evaluation of inflammation Early studies evaluating the prognostic impact of an inflammatory infiltrate in breast cancer reported conflicting results, with some showing an association with improved survival and others showing an association with worse outcome (reviewed by Mohammed [7]). These studies were heterogeneous with respect to the methodology used to identify inflammation, patient population and length of follow-up. In a recently published study, Rakha and colleagues correlated the degree of tumor-associated inflammation with known prognostic characteristics, as well as survival outcomes [8]. The study included 1597 patients treated with definitive surgery between 1974 and 1988. No patients received adjuvant chemotherapy or endocrine therapy, allowing investigators to evaluate the effects of inflammation on the natural history of disease. Pathologic evaluation included determination of histology, the presence of lymphovascular invasion, tumor grade and hormone receptor status. The intensity of inflammation determined on hematoxylin and eosin (H&E) sections CENPA was absent or minimal in 72%, mild in 18%, moderate in 8% and marked in 2% of cases. For survival analyses, moderate and marked inflammation were categorized together as prominent, and on both univariate and multivariate analyses, prominent inflammation correlated with improved overall survival (OS) and recurrence-free survival (RFS). Grade 3 carcinomas with prominent inflammation had improved OS compared with those without. Interestingly, patients with grade 2 carcinomas with absent or mild inflammation had worse OS than grade 3 carcinomas with prominent inflammation [8]. These data are consistent with other studies JTE-952 showing that a strong lymphocytic infiltrate is associated with good clinical outcomes in various other solid tumor types [9]. Additional studies have evaluated the prognostic significance of lymphocytic infiltration in particular subtypes of breast cancer. A study from Liu evaluated TILs on a tissue microarray constructed from over 3990 breast tumors [10]. On multivariate analysis, the presence of TILs was an independent prognostic factor associated with improved breast-cancer-specific survival for patients with basal-like breast cancer, which they defined as being estrogen receptor (ER)-, progesterone receptor- and HER2-negative, and either CK5/6 or EGF receptor-positive. A study from Alexe evaluated patients with node-negative, HER2-overexpressing breast cancer, and found that patients with tumors with a marked lymphocytic infiltrate had significantly improved rates of distant metastasis-free survival [11]. Taken together, these data suggest that the immune response in the tumor microenvironment of both HER2+ and basal tumors is an important prognostic factor that could potentially be used to stratify high- or low-risk patients within these subgroups for inclusion in future clinical trials, or to identify patients to enroll into trials evaluating immunotherapeutic agents. JTE-952 Gene-expression profiles Improvements in microarrays have allowed investigators to identify gene-expression profiles that provide prognostic information in breast cancer [12,13]. Several investigators have evaluated prognostic gene signatures that include immune markers. Desmedt and colleagues performed a comprehensive meta-analysis integrating previously JTE-952 published gene-expression data with clinicopathologic data focusing on defined molecular subtypes [14]. They developed gene-expression modules related to key biologic processes, including proliferation, angiogenesis, apoptosis, tumor invasion, ER and HER2 signaling, and immune response. For the ER+/HER2? subgroup, histologic grade and the proliferation gene module were prognostic. In HER2+ tumors, tumor invasion and immune response gene.