Abstract 338P
Background
Cancer development is aggravated by a rare population of cells, termed cancer stem cells (CSCs), that uniquely initiates and sustains the disease. Although CSCs can orchestrate the immune systems in favour of tumor, the detailed mechanisms underlying their immunomodulatory effects remain elusive. Recent reports indicate the contribution of exosomes, secreted from various cells, as mediators of cell-to-cell communication and also as a mediator of immune modulation in the tumor microenvironment.
Methods
Breast CSCs (bCSCs) were purified from breast cancer cell lines and human breast tumor tissues following which CSC-derived exosomes (CDEs) were isolated. Peripheral blood mononuclear cells were isolated from the blood of healthy donors and breast cancer patients, co-cultured with CDEs, and T regulatory (Treg) cell generation was evaluated.
Results
We found that bCSCs are able to generate CD4+CD25+FOXP3+ Treg cells having suppressive activity. Our search for the underlying mechanism revealed for the first time that bCSC-secreted exosomes contain FOXP3 protein that uniquely initiates acquisition of Treg characteristics in the infiltrating T lymphocytes. Exosomes from FOXP3-ablated bCSCs failed to augment Treg cell generation indicating the requirement of bCSC-gifted FOXP3 in Treg generation. Interestingly, perturbation of transcription or translation in T naïve cells significantly decreased CDE-augmented FOXP3 level signifying that CDE-FOXP3 utilizes the transcription and translational machineries of T naïve cells to induce Treg cell generation. In fact, exosome-shuttled FOXP3 binds to the CNS2 region of the Foxp3 promoter in T lymphocytes, thus resulting in a sustained expression of FOXP3 and further leading to induction of other genes of Foxp3 interactome, thereby phenotypically converting the T cells to Treg cells.
Conclusions
Collectively our data demonstrates that bCSC-shed exosomal FOXP3 plays an important role in procreation of Treg cells within the tumor microenvironment thus leading to tumor-induced immune suppression. Breaching the deadly-liaison between them might be a promising strategy for breast cancer therapy.
Clinical trial identification
Editorial acknowledgement
Legal entity responsible for the study
Prof. Tanya Das, Professor, Division of Molecular Medicine, Bose Institute.
Funding
Department of Science and Technology, Govt. of Inda Council of Scientific & Industrial Research (CSIR), Govt. of India.
Disclosure
All authors have declared no conflicts of interest.
Resources from the same session
164P - Multi-centered phase II trial of weekly 5-FU plus l-LV regimen as salvage line chemotherapy for oral fluorouracil resistant advanced gastric cancer (HGCSG1502)
Presenter: Yusuke Sasaki
Session: Poster display session
Resources:
Abstract
165P - Lenvatinib treatment for advanced hepatocellular carcinoma: The relationship between efficacy and safety
Presenter: Takayoshi Oikawa
Session: Poster display session
Resources:
Abstract
166P - The comparison between UGT1A1 single heterozygous and wild type regarding the clinical outcomes of fixed dose irinotecan monotherapy for advanced gastric cancer: Multicenter retrospective study
Presenter: Takahide Sasaki
Session: Poster display session
Resources:
Abstract
167P - Prognostic impact of the C-reactive protein/albumin ratio in advanced pancreatic cancer treated with GEM plus nab-PTX or FOLFIRINOX: Based on the results of a multicenter retrospective study (the NAPOLEON study)
Presenter: Akitaka Makiyama
Session: Poster display session
Resources:
Abstract
168P - A retrospective multicenter study evaluating the efficacy and safety of irinotecan in patients with advanced gastric cancer: Analysis of Glasgow Prognostic Score (GPS)
Presenter: Takuya Honda
Session: Poster display session
Resources:
Abstract
169P - M-phase phosphoprotein 8 promotes gastric cancer growth and metastasis via p53/Bcl-2 and EMT-related signalling pathways
Presenter: Yizhuo Wang
Session: Poster display session
Resources:
Abstract
170P - Surgery alone versus surgery combined with Chemotherapy: Survival patterns among patients with fibrolamellar hepatocellular carcinoma
Presenter: Yasmine Ashraf
Session: Poster display session
Resources:
Abstract
171P - The clinical value of prognostic nutritional index in patients with anastomotic leakage after minimally invasive esophagectomy
Presenter: Yan Wang
Session: Poster display session
Resources:
Abstract
172P - Preoperative neutrophil‐to‐lymphocyte ratio (NLR) predicts recurrence after surgery in patient with pancreatic neuroendocrine neoplasm (PanNEN)
Presenter: Takayuki Miura
Session: Poster display session
Resources:
Abstract
173P - Cancer stem-like phenotypes including immune surveillance and its responsible genes in induced liver cancer stem-like cells
Presenter: Ryouichi Tsunedomi
Session: Poster display session
Resources:
Abstract