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
15P - Comparing the outcomes of the mastectomy using the tumescent technique by between the special and non-special surgeons
Presenter: Naoya Takeda
Session: Poster display session
Resources:
Abstract
16P - Risk factors and prognostic value of non-alcoholic fatty liver disease (NAFLD) in hormone positive, non-metastatic breast cancer receiving adjuvant hormonal therapy
Presenter: Kartika Taroeno Hariadi
Session: Poster display session
Resources:
Abstract
17P - Distance related outcome in indigenous and non-indigenous breast cancer women of Western Australia
Presenter: Azim Khan
Session: Poster display session
Resources:
Abstract
18P - Usefulness of neutrophil to lymphocyte ratio in early stage breast cancer as predictor of disease-free survival in a Babylon Oncology Center
Presenter: Yaala Raof Al-Bairmany
Session: Poster display session
Resources:
Abstract
19P - Silymarin functionalized quantum cores as selective inhibitor of polo-like kinase 1, and preclinical antitumor activity in human breast cancer xenografts
Presenter: Manickam Paulpandi
Session: Poster display session
Resources:
Abstract
20P - Diagnostic value of serum HER-2 level in compression with tissue HER-2 in breast cancer: A systematic review and meta-analysis
Presenter: Amir Shamshirian
Session: Poster display session
Resources:
Abstract
21P - Clinical outcome of treatment without trastuzumab in HER2 positive breast cancer patients
Presenter: Than Than Aye
Session: Poster display session
Resources:
Abstract
22P - Clinical outcomes after skin-sparing or nipple areolar complex-sparing mastectomy with sentinel lymph node biopsy in early breast cancer patients
Presenter: Hye Yoon Lee
Session: Poster display session
Resources:
Abstract
23P - The correlations between knowledge and attitudes of productive age women toward “SADARI” (breast self-assessment) as early detection of breast cancer in Pejeng Kaja Village, Ubud, Bali
Presenter: Yorky Brahmantya
Session: Poster display session
Resources:
Abstract
24TiP - KEYNOTE-756: A randomized, double-blind, phase III study of pembrolizumab or placebo with neoadjuvant chemotherapy and adjuvant endocrine therapy for high-risk, early-stage, ER+/HER2−breast cancer
Presenter: Fatima Cardoso
Session: Poster display session
Resources:
Abstract