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

Abstract

BackgroundNeoadjuvant 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.MethodsGiven 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.ResultsBy 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.ConclusionsGene 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.Electronic supplementary materialThe online version of this article (doi:10.1186/s13073-014-0080-8) contains supplementary material, which is available to authorized users.

Tumor mutational burden is a determinant of immune-mediated survival in breast cancer

“…Multivariable analyses have shown that high metagene values (equating with abundant immune infiltrates) are significantly and independently associated with prolonged distant metastasis-free survival of breast cancer patients 19,21 as well as a greater likelihood of pathologic response to neoadjuvant chemotherapy. 20 These findings are consistent with functional roles for the metagene-associated leukocytes in protective anti-tumor immunity, namely cytolytic activity (T/NK), antigen presentation (M/D) and humoral response (B/P).…”

Intratumoral injection of a CpG oligonucleotide reverts resistance to PD-1 blockade by expanding multifunctional CD8 + T cells

“…Many clinical studies have shown a positive correlation between B cells and long-term survival in breast, colon, and nonsmall lung cancer (22)(23)(24)(25). In other studies, the presence of B-cell signature correlates with responsiveness to IL-2 (26), ipilumimab (27), and anti-Her2/neu (28). We show that neutralization of CXCL13, which significantly decreased B-cell infiltration within the tumor (9) (Fig.…”

Immunogenic Subtypes of Breast Cancer Delineated by Gene Classifiers of Immune Responsiveness

“…Through hierarchical clustering analysis, we and others have demonstrated that these genes self-organize into multiple gene clusters that embody signaling networks fundamental to distinct and identifiable immune cell subpopulations (12-18). These immune gene signatures or “metagenes”, consistent with the effector cell types they reflect, have been shown by multiple groups to be associated with patient outcomes such as disease-free and overall survival (2, 8, 12, 13, 16, 19-21), response to neoadjuvant chemotherapy (22, 23) and adjuvant molecular therapy (anti-Her2/neu) (24) paralleling historical immunohistochemical observations.…”

“…The expression scores of all three metagenes were significantly associated with prolonged distant metastasis-free survival (DMFS) of breast cancer patients and displayed additive prognostic information when considered in multivariate Cox regression models. We have also observed that these same prognostic immune metagenes are predictive of taxane and anthracycline efficacy in the neoadjuvant setting (22). …”