Interactions between immunity, proliferation and molecular subtype in breast cancer prognosis

Abstract

BackgroundGene expression signatures indicative of tumor proliferative capacity and tumor-immune cell interactions have emerged as principal biology-driven predictors of breast cancer outcomes. How these signatures relate to one another in biological and prognostic contexts remains to be clarified.ResultsTo investigate the relationship between proliferation and immune gene signatures, we analyzed an integrated dataset of 1,954 clinically annotated breast tumor expression profiles randomized into training and test sets to allow two-way discovery and validation of gene-survival associations. Hierarchical clustering revealed a large cluster of distant metastasis-free survival-associated genes with known immunological functions that further partitioned into three distinct immune metagenes likely reflecting B cells and/or plasma cells; T cells and natural killer cells; and monocytes and/or dendritic cells. A proliferation metagene allowed stratification of cases into proliferation tertiles. The prognostic strength of these metagenes was largely restricted to tumors within the highest proliferation tertile, though intrinsic subtype-specific differences were observed in the intermediate and low proliferation tertiles. In highly proliferative tumors, high tertile immune metagene expression equated with markedly reduced risk of metastasis whereas tumors with low tertile expression of any one of the three immune metagenes were associated with poor outcome despite higher expression of the other two metagenes.ConclusionsThese findings suggest that a productive interplay among multiple immune cell types at the tumor site promotes long-term anti-metastatic immunity in a proliferation-dependent manner. The emergence of a subset of effective immune responders among highly proliferative tumors has novel prognostic ramifications.

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

“…The immune metagene model (IMM) is a survival-based prognostic classification system for the objective assignment of patients to the immune subclasses FID, WID or PID (reflecting favorable, weak or poor immunogenic dispositions, respectively) as previously described. 19,21 Sample classification relies on the relative expression levels (metagene scores) of the immune gene signatures (metagenes) which reflect the intratumoral presence of three immune cell types: B cells/plasma cells (B/P metagene) marked by IgG antibody isotype-related genes; T cells/NK cells (T/NK metagene) comprised mainly of genes with functional roles in Cytotoxic T-cell activation/helper T-cell type 1 (Th1) signaling, and Myeloid/Dendritic cells (M/D metagene) delineated by genes encoding myeloid-specific and MHC-class II antigen-presenting molecules. The genes comprising each metagene are defined in Additional File 6 of Nagalla and coworkers 19 and were mapped to the TCGA and METABRIC data sets by gene symbol.…”

“…Tumors were assigned to immune subclasses according to the following tertile configurations: 1) FID: having metagene scores in the upper tertile of all three metagenes, simultaneously; 2) PID: having metagene scores in the lower tertile of one or more metagenes; and 3) WID: having metagene scores of both intermediate and upper metagene tertiles (but not classifying as FID or PID). 19 Immune subclass assignments are provided in eWorksheet 1 in Supplement 2.…”

“…The immune metagenes were originally defined according to the Affymetrix U133A expression profiling platform using a breast cancer meta-dataset (termed “MC1”) of 1,954 tumor expression profiles 19 , then adapted to the TCGA RNAseq data set and the METABRIC cohort Illumina BeadChip data set. We compared metagene distributions among the 3 datasets (eFigure 4 in Supplement 1).…”

“…14–18 In a recent report, we described three such prognostic immune signatures in breast tumors, each comprised of tens of genes with immune-specialized functions and expression patterns unique to immune cell populations. 19–21 These signatures, or metagenes, reflect the intratumoral presence of different immune cell lineages: T cells/NK cells (T/NK metagene) comprised of genes with functional roles in cytotoxic T-cell and NK-cell activation, B cells/plasma cells (B/P metagene) marked by IgG antibody isotype-related genes, and Myeloid/Dendritic cells (M/D metagene) delineated by genes encoding myeloid-specific and MHC-class II antigen-presenting molecules. 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.…”

“…19–21 These signatures, or metagenes, reflect the intratumoral presence of different immune cell lineages: T cells/NK cells (T/NK metagene) comprised of genes with functional roles in cytotoxic T-cell and NK-cell activation, B cells/plasma cells (B/P metagene) marked by IgG antibody isotype-related genes, and Myeloid/Dendritic cells (M/D metagene) delineated by genes encoding myeloid-specific and MHC-class II antigen-presenting molecules. 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).…”