Among these were 3 breast cancer data sets for which information in regards to clinical neoadjuvant chemotherapy response was available that were used to test metagenes predictive capabilities. The reproducibility of stress-related metagenes was found to be generally poor—perhaps suggesting a lack of coordinated and persistent stress-related events in pre-treatment tumor deposits—such that no association between these metagenes and clinical outcome was detected. However, the immune-related metagene driven by the CXC motif chemokine ligand, CXCL13 transcript bore the highest reproducibility across data sets and was strongly associated with the achievement of complete pathological response. Genes embraced by the CXCL13 metagenes12 largely overlap with those associated with favorable cancer prognosis and response to immunotherapy. 3, 4 They include classical ICR genes such as ligands for the chemokine receptors CXCR3 and CCR5 (CXCL9–10, and CCL5 transcripts, respectively), immuneeffector genes (eg, PRF1, granzymes), and Th-1 related genes (IFNG and CD8B). 12 To explain the favorable predictive role of Th-1 like gene signatures in the setting of cancer immunotherapy, it has been proposed that immune-manipulation could restore a naturally occurring, though insufficient, host’s immune response by enhancing its effector functions and, thus, its predictive significance. 4 Similarly, it is tempting to hypothesize that the immunogenic cell death, eventually induced by antineoplastic drugs, requires the presence of an ongoing intratumoral response to exert its immune-adjuvant effect. A number of investigations have reported a correlation between T-cell infiltrates, Th-1 related genes, and achievement of complete response following neoadjuvant chemotherapy in breast cancer patients. 15 By defining the CXCL13-meta gene, Stoll et al. added molecular precision to previous observations. 15, 16 In fact, only recently, has CXCL13 emerged as critical modulator of intratumoral response. 17-19 This chemokine, which binds CXCR5, is physiologically highly expressed in the follicles of secondary lymphoid organs, where it can be secreted by follicular dendritic cells and T follicular helper (Tfh) cells. In this context, CXCL13 mediates migration of high-affinity CXCR5+ Tfh cells and B cells into B-cell concentrated areas. While a number of studies have reported the presence of tertiary lymphoid structure in a considerable proportion of cancers, 20 it was only last year that the presence of CXCL13+ Tfh cells were demonstrated in solid tumors. 18 By analyzing breast cancer samples, Gu-Trantien et al. 17 showed that the presence of tumorinfiltrating CXCL13+ Tfh cells, localizing primarily in peritumoral tertiary lymphoid structures, was associated with improved disease outcome. In parallel, the presence of Tfh cells were shown to correlate with abundance of Th1 cells and B cells within the neoplastic bed. 17 Similar conclusions were recently independently reached by Bindea et al. 19 via analysis of colorectal tumor specimens. Interestingly, authors showed that tumor cells also expressed CXCL13 and that genetic deletion of CXCL13 markedly lowers the density of B cells and Tfh cells in invasive margins. 19 It remains, however, to be fully elucidated whether (and how) the genetic makeup of the host, somatic cancer cell genetic or epigenetic aberrations, or environmental factors, such as lifetime exposure to commensale microbiota, 21 may interact to influence the development of a favorable cancer immune phenotype. We believe that assessing these critical questions using integrated high-throughput approaches will allow the …