Article

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
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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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    • "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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    • "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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