As for FOXP3, it should be noted that this molecule can be expressed by T-regulatory cells, but also by activated T cells and breast cancer cells, adding complexity to the functional interpretation of gene expression studies [39,54,55].
Results from the NeoALTTO trial have recently shown that TIL density predicts response to neoadjuvant chemotherapeutic regimens containing the anti-HER2 monoclonal antibody trastuzumab or the HER1/HER2 inhibitor lapatinib . Finally, preliminary results from two other clinical trials in patients treated with anti-HER2-based neoadjuvant chemotherapy found a positive correlation between pCR and the expression of plasma cell genes  or immune-function metagenes (i.e. PD-1 and STAT1) .
It is presently unclear how an immunologically active microenvironment can enhance the efficacy of antineoplastic drugs. It has been proposed that certain chemotherapeutic agents such as cyclophosphamide, doxorubicin, and oxaliplatin may act as immune adjuvants by inducing an immunogenic cell death through the stimulation of dendritic cell-mediated uptake of apoptotic corpses and consequent enhancement of antigen-specific T-cell response . According to this model, the elicitation of a more effective antitumoral response following chemotherapy in tumors bearing a subacute inflammatory status could contribute to a more effective tumor clearance. Recently, Sistigu et al.[60▪] proved that anthracyclines can directly stimulate the rapid production of type I interferon by cancer cells with subsequent release of the CXCL10 chemokine through the activation of autocrine and paracrine loops. Vice versa, IFN-γ release by activated T cells could enhance the cytotoxic activity of chemotherapeutic agents by modulating IFN-inducible molecules involved in DNA-damage repair, even though no solid data exist to date to support this latter hypothesis. As for the findings from trastuzumab studies, it is plausible that an active immune microenvironment could potentiate the elimination of residual disease via antibody-dependent cell-mediated cytotoxicity.
As discussed, different performances among proposed immune signatures have been observed, hindering their development toward clinical application. Optimization and validation of immune gene signatures could have a dramatic impact on clinical practice. For example, in ER+ node-negative tumors classified at medium or high risk of relapse by conventional molecular prognostic indices centered on proliferation indexes (e.g. Oncotype-Dx ‘Recurrence Score’, Genomic Health, Inc., Redwood City, California, USA), immune gene scores could define a novel category of low-risk patients for whom chemotherapy could be omitted. In HER2+ tumors, it is plausible that immune signatures could be used to identify patients who will not benefit from trastuzumab and for whom other therapeutic approaches could be tested (e.g. combination of trastuzumab and PD-1 inhibitor  or the less immune-dependent anti-HER2 therapy as trastuzumab–emtansine) [42▪▪,62]. Similarly, they could be used to assign patients unlikely to benefit from conventional neoadjuvant chemotherapy to experimental approaches or to define those patients who will benefit from carboplatin-containing regimens. In the metastatic setting, it is plausible that immune gene signatures may better define patients likely to benefit from PD-1 blockade, particularly those signatures that dually incorporate measures of immunosuppressive markers, for which more research is needed.
Although the rate and duration of clinical responses in these two trials were encouraging, the majority of patients (70–80%) were completely refractory to treatment [63,64]. Hence, it is expected that immunogenomic studies will elucidate the mechanisms that prevent or promote the development of a favorable antitumoral immunity. Such mechanisms could then be targeted to reprogram the microenviroment toward an immune permissive one, resulting in an enhanced efficacy of immunotherapeutic approaches .
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