Lisa Speigl1, Helen Burow2, Jithendra Kini Bailur1,3, Nicole Janssen1, Christina-Barbara Walter2, Graham Pawelec1,4,5,6, Christopher Shipp7,8. 1. Department of Internal Medicine II, University Hospital Tübingen, Waldhörnlestraße 22, 72072, Tübingen, Germany. 2. Department of Obstetrics and Gynecology, University Hospital Tübingen, Calwerstraße 7, 72076, Tübingen, Germany. 3. Yale Cancer Center, Yale University School of Medicine, 333 Cedar St, New Haven, USA. 4. John van Geest Cancer Research Centre, Nottingham Trent University, College Dr, Clifton, Nottingham, NG11 8NS, UK. 5. Division of Cancer Studies, King's College London, Strand, London, WC2R 2LS, UK. 6. Health Sciences North Research Institute, 41 Ramsey Lake Road, Sudbury, ON, Canada. 7. Department of Internal Medicine II, University Hospital Tübingen, Waldhörnlestraße 22, 72072, Tübingen, Germany. mrchristophershipp@gmail.com. 8. Natural and Medical Sciences Institute (NMI) at the University of Tübingen, Markwiesenstraße 55, 72770, Reutlingen, Germany. mrchristophershipp@gmail.com.
Abstract
PURPOSE: Despite the recent expansion in the use of immunotherapy for many cancer types, it is still not a standard treatment for breast cancer. Identifying differences in the immune systems of breast cancer patients compared to healthy women might provide insight into potential targets for immunotherapy and thus may assist its clinical implementation. METHODS: Multi-colour flow cytometry was used to investigate myeloid and lymphoid populations in the peripheral blood of breast cancer patients (n = 40) and in the blood of healthy age-matched women (n = 25). We additionally performed functional testing to identify immune suppressive mechanisms used by circulating CD14+ myeloid cells from breast cancer patients. RESULTS: Our results show that breast cancer patients have significantly elevated frequencies of cells with the monocytic myeloid-derived suppressor cell (mMDSC) phenotype CD14+ HLA-DR-/low compared with healthy women (p < 0.01). We also observed higher levels of earlier differentiated T cells and correspondingly lower levels of T cells in later stages of differentiation (p < 0.05). These disease-associated differences could already be detected in early-stage breast cancer patients in stages 1 and 2 (n = 33 of 40) (p < 0.05). Levels of circulating T cells correlated with certain clinical features and with patient age (p < 0.05). Functional tests showed that CD14+ myeloid cells from breast cancer patients more potently suppressed autologous T cell proliferation than CD14+ cells from healthy women (p < 0.01). Subsequent investigation determined that suppression was mediated in part by reactive oxygen species, because inhibiting this pathway partially restored T cell proliferation (p < 0.01). CONCLUSION: Our results highlight the potential importance of cells with mMDSC phenotypes in breast cancer, identifiable already at early stages of disease. This may provide a basis for identifying possible new therapeutic targets to enhance anti-cancer immunity.
PURPOSE: Despite the recent expansion in the use of immunotherapy for many cancer types, it is still not a standard treatment for breast cancer. Identifying differences in the immune systems of breast cancerpatients compared to healthy women might provide insight into potential targets for immunotherapy and thus may assist its clinical implementation. METHODS: Multi-colour flow cytometry was used to investigate myeloid and lymphoid populations in the peripheral blood of breast cancerpatients (n = 40) and in the blood of healthy age-matched women (n = 25). We additionally performed functional testing to identify immune suppressive mechanisms used by circulating CD14+ myeloid cells from breast cancerpatients. RESULTS: Our results show that breast cancerpatients have significantly elevated frequencies of cells with the monocytic myeloid-derived suppressor cell (mMDSC) phenotype CD14+ HLA-DR-/low compared with healthy women (p < 0.01). We also observed higher levels of earlier differentiated T cells and correspondingly lower levels of T cells in later stages of differentiation (p < 0.05). These disease-associated differences could already be detected in early-stage breast cancerpatients in stages 1 and 2 (n = 33 of 40) (p < 0.05). Levels of circulating T cells correlated with certain clinical features and with patient age (p < 0.05). Functional tests showed that CD14+ myeloid cells from breast cancerpatients more potently suppressed autologous T cell proliferation than CD14+ cells from healthy women (p < 0.01). Subsequent investigation determined that suppression was mediated in part by reactive oxygen species, because inhibiting this pathway partially restored T cell proliferation (p < 0.01). CONCLUSION: Our results highlight the potential importance of cells with mMDSC phenotypes in breast cancer, identifiable already at early stages of disease. This may provide a basis for identifying possible new therapeutic targets to enhance anti-cancer immunity.
Entities:
Keywords:
Breast cancer; MDSCs; Periphery; ROS; T cells
Authors: Gemma A Foulds; Jayakumar Vadakekolathu; Tarek M A Abdel-Fatah; Divya Nagarajan; Stephen Reeder; Catherine Johnson; Simon Hood; Paul M Moseley; Stephen Y T Chan; A Graham Pockley; Sergio Rutella; Stephanie E B McArdle Journal: Front Immunol Date: 2018-09-11 Impact factor: 7.561