Leukocyte composition of human breast cancer

Department of Pathology and Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, CA 94143, USA.
Proceedings of the National Academy of Sciences (Impact Factor: 9.81). 08/2011; 109(8):2796-801. DOI: 10.1073/pnas.1104303108
Source: PubMed

ABSTRACT Retrospective clinical studies have used immune-based biomarkers, alone or in combination, to predict survival outcomes for women with breast cancer (BC); however, the limitations inherent to immunohistochemical analyses prevent comprehensive descriptions of leukocytic infiltrates, as well as evaluation of the functional state of leukocytes in BC stroma. To more fully evaluate this complexity, and to gain insight into immune responses after chemotherapy (CTX), we prospectively evaluated tumor and nonadjacent normal breast tissue from women with BC, who either had or had not received neoadjuvant CTX before surgery. Tissues were evaluated by polychromatic flow cytometry in combination with confocal immunofluorescence and immunohistochemical analysis of tissue sections. These studies revealed that activated T lymphocytes predominate in tumor tissue, whereas myeloid lineage cells are more prominant in "normal" breast tissue. Notably, residual tumors from an unselected group of BC patients treated with neoadjuvant CTX contained increased percentages of infiltrating myeloid cells, accompanied by an increased CD8/CD4 T-cell ratio and higher numbers of granzyme B-expressing cells, compared with tumors removed from patients treated primarily by surgery alone. These data provide an initial evaluation of differences in the immune microenvironment of BC compared with nonadjacent normal tissue and reveal the degree to which CTX may alter the complexity and presence of selective subsets of immune cells in tumors previously treated in the neoadjuvant setting.

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Available from: Alfred Au, Jan 14, 2015
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    • "In this study, we identified a Th2 biased gene expression of the intratumoral CD4+ T cells, which has previously been shown to suppress the anti-tumor immunity of the host [10] [11] [12] [33]. By integrating the DE genes of the intratumoral CD4+ T cells (CD4 DEGs) with the DE genes of the bulk BC tissues (BC DEGs), we identified five dysregulated cytokines as the predictor to reflect the Th2 polarization of the intratumoral CD4+ T cells, which in turn could be used to predict the immune-polarization side effects of tamoxifen treatment. "
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    ABSTRACT: Factors within the tissue of breast cancer (BC) may shift the polarization of CD4+ T cells towards Th2 direction. This tendency can promote tumor development and be enhanced by the use of tamoxifen during the treatment. Thus, the patients with low levels of tumor-induced Th2 polarization prior to tamoxifen treatment may better endure the immune-polarizing side effects (IPSE) of tamoxifen and have better prognoses. Estimation of Th2 polarization status should help predict the IPSE among tamoxifen-treated patients and guide the use of tamoxifen among all BC patients before the tamoxifen therapy. Here, we report profiling of differentially expressed (DE) intratumoral cytokines as a signature to evaluate the IPSE of tamoxifen. The DE genes of intratumoral CD4+ T cells (CD4 DEGs) were identified by gene expression profiles of purified CD4+ T cells from BC patients and validated by profiling of cultured intratumoral CD4+ T cells. Functional enrichment analyses showed a directed Th2 polarization of intratu-moral CD4+ T cells. To find the factors inducing the Th2 polarization of CD4+ T cells, we identified 995 common DE genes of bulk BC tissues (BC DEGs) by integrating five independent datasets. Five DE cytokines observed in bulk BC tissues with dysregulated receptors in the intratumoral CD4+ T cells were selected as the predictor of the IPSE of tamoxifen. The patients predicted to suffer low IPSE (low Th2 polarization) had a significantly lower distant relapse risk than the patients predicted to suffer high IPSE in independent datasets (n = 608; HR = 4.326, P = 0.000897; HR = 2.014, P = 0.0173; HR = 2.72, P = 0.04077). Patients predicted to suffer low IPSE would benefit from tamoxi-fen treatment (HR = 2.908, P = 0.03905). The DE intratumoral cytokines identified in this study may help predict the IPSE of tamoxifen and justify the use of tamoxifen in BC treatment.
    American Journal of Cancer Research 02/2015; 5(2):726-737. · 3.97 Impact Factor
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    • "Thus, paclitaxel-based neoadjuvant chemotherapy has been shown to increase the frequency of HE-detectable BC-infiltrating lymphocytes, more so in patients who responded to chemotherapy (Demaria et al., 2001). Moreover, accumulating evidence indicates that chemotherapy stimulates the infiltration of BCs by myeloid and granzyme B-expressing cells while increasing the intratumoral CD8 + to CD4 + T cell ratio (Ruffell et al., 2012). Of note, an elevation in the intratumoral CD8 + to FOXP3 + T cell ratio after one single cycle of anthracycline-based neoadjuvant chemotherapy predicts the pCR to the entire chemotherapeutic regimen (six cycles) (Ladoire et al., 2011; Senovilla et al., 2012). "
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    ABSTRACT: Conventional chemotherapeutics and targeted antineoplastic agents have been developed based on the simplistic notion that cancer constitutes a cell-autonomous genetic or epigenetic disease. However, it is becoming clear that many of the available anticancer drugs that have collectively saved millions of life-years mediate therapeutic effects by eliciting de novo or reactivating pre-existing tumor-specific immune responses. Here, we discuss the capacity of both conventional and targeted anticancer therapies to enhance the immunogenic properties of malignant cells and to stimulate immune effector cells, either directly or by subverting the immunosuppressive circuitries that preclude antitumor immune responses in cancer patients. Accumulating evidence indicates that the therapeutic efficacy of several antineoplastic agents relies on their capacity to influence the tumor-host interaction, tipping the balance toward the activation of an immune response specific for malignant cells. We surmise that the development of successful anticancer therapies will be improved and accelerated by the immunological characterization of candidate agents.
    Immunity 07/2013; 39(1):74-88. DOI:10.1016/j.immuni.2013.06.014 · 19.75 Impact Factor
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    • "The detection of higher amounts of cytokines like TGF-beta [32], M-CSF [33], and IL-6 [34] [35] in patients' serum could suggest that the tumor presence affects cells in distant organs, thus resulting in systemic alterations which could allow tumors not only to grow locally unchecked but also to metastasize without an effective immune barrier. In agreement with that are: the higher frequency of myeloidderived suppressor cells (MDSCs) (a group of immature but potent suppressor cells capable of down-regulating anti-tumor immunity) found in cancer patients' circulation [36]; the decreased frequency of circulating and tumorinfiltrating myeloid DCs [37] [38]; and the CD4 lymphopenia observed in cancer patients [39] [40] [41]; all three important alterations of immune homeostasis in cancer patients that, consequently, hamper the effectiveness of their treatment. "
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    ABSTRACT: Dendritic cells (DCs) are essential for the maintenance of homeostasis in the organism, and they do that by modulating lymphocyte priming, expansion, and response patterns according to signals they receive from the environment. The induction of suppressive lymphocytes by DCs is essential to hinder the development of autoimmune diseases but can be reverted against homeostasis when in the context of neoplasia. In this setting, the induction of suppressive or regulatory T cells contributes to the establishment of a state of tolerance towards the tumor, allowing it to grow unchecked by an otherwise functional immune system. Besides affecting its local environment, tumor also has been described as potent sources of anti-inflammatory/suppressive factors, which may act systemically, generating defects in the differentiation and maturation of immune cells, far beyond the immediate vicinity of the tumor mass. Cytokines, as IL-10 and TGF-beta, as well as cell surface molecules like PD-L1 and ICOS seem to be significantly involved in the redirection of DCs towards tolerance induction, and recent data suggest that tumor cells may, indeed, modulate distinct DCs subpopulations through the involvement of these molecules. It is to be expected that the identification of such molecules should provide molecular targets for more effective immunotherapeutic approaches to cancer.
    Clinical and Developmental Immunology 05/2013; 2013:806025. DOI:10.1155/2013/806025 · 2.93 Impact Factor
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