Leukocyte Complexity Predicts Breast Cancer Survival and Functionally Regulates Response to Chemotherapy

By Lisa M. Coussens, Helen Diller, D. DeNardo, D. Brennan, E. Rexhepaj, B. Ruffell, S. Shiao, S. Madden, W. Gallagher, N. Wadhwani and 7 more. Cancer Discovery, 2011

1,634 citations recorded by the source corpus.

Immune-regulated pathways influence multiple aspects of cancer development. In this article we demonstrate that both macrophage abundance and T-cell abundance in breast cancer represent prognostic indicators for recurrence-free and overall survival. We provide evidence that response to chemotherapy is in part regulated by these leukocytes; cytotoxic therapies induce mammary epithelial cells to produce monocyte/macrophage recruitment factors, including colony stimulating factor 1 (CSF1) and interleukin-34, which together enhance CSF1 receptor (CSF1R)–dependent macrophage infiltration. Blockade of macrophage recruitment with CSF1R-signaling antagonists, in combination with paclitaxel, improved survival of mammary tumor–bearing mice by slowing primary tumor development and reducing pulmonary metastasis. These improved aspects of mammary carcinogenesis were accompanied by decreased vessel density and appearance of antitumor immune programs fostering tumor suppression in a CD8+ T-cell–dependent manner. These data provide a rationale for targeting macrophage recruitment/ response pathways, notably CSF1R, in combination with cytotoxic therapy, and identification of a breast cancer population likely to benefit from this novel therapeutic approach.

Subfields: Immunology, Molecular Biology, Oncology

View Paper: https://www.semanticscholar.org/paper/131fd58e4011eb1888eead4390d39bba372b72e1

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Citations in the corpus

Immune-based mechanisms of cytotoxic chemotherapy: implications for the design of novel and rationale-based combined treatments against cancer (2013, background): “Conversely, paclitaxel-induced influx of TAMs was detrimental to chemotherapy response in mouse mammary carcinoma and breast cancer patients.(18,19)”
Differential Macrophage Programming in the Tumor Microenvironment (2012, neutral): “, MMTV-PyMT mice [49], a property that has thus far not been observed in tumors following blockade of TAM infiltration [50], or by myeloidspecific Vegfa ablation [37], thus hinting at a unique mode of action either downstream or parallel to VEGFA bioactivity [48].”
Vascular normalizing doses of antiangiogenic treatment reprogram the immunosuppressive tumor microenvironment and enhance immunotherapy (2012, background): “Emerging data indicate that abnormal tumor vasculature, resulting from the prevalence of pro- versus antiangiogenic signals, fosters an immunosuppressive tumor microenvironment that enables the tumor to evade host immunosurveillance (4, 6, 9).”
Vascular normalization as an emerging strategy to enhance cancer immunotherapy (2013, neutral): “Indeed, both preclinical and clinical reports found relative absence of anti-tumor lymphocytes, but detected abundant regulatory immune cells such as tumor-associated macrophages (TAMs) and regulatory T cells (Tregs) (4, 8, 10-13).”
Stroma Cells in Tumor Microenvironment and Breast Cancer (2012, neutral): “In breast cancer, infiltrating TAMs correlate with poor prognostic features [97, 109], higher tumor grade [99], high vascular grade, increased necrosis [101], and decreased disease-free survival [100, 101] and overall survival [101].”