Inactivity of cytotoxic T lymphocytes (CTLs) in the tumor microenvironment allows an aggressive progression of breast cancer (BC). Multiple cells and factors have been reported to contribute to the arrest of the antitumor response of cytotoxic T lymphocytes (CTL) in the tumor microenvironment. Tumor-derived exosomes (TDEs) play a key role in tumor-host crosstalk and that exosome secretion, composition, and functional capacity are altered as tumors progress. How these TDEs regulate CTL function is still not clear. This study addresses a mechanism that TDEs follow to modulate CTL activity in the tumor microenvironment.
Breast cancer patient serum, MDA-MB 231 cell derived exosomes were characterized by Dynamic Light Scattering (DLS) and western blot analysis. Sorted CD8+ T cells from PBMC of healthy volunteers were activated with CD3/CD28, recombinant IL2 and treated with TDEs for different timespans. Exosome uptake by T cells was studied by confocal microscopy. Cell proliferation and differentiation was studied by flow cytometry analysis. qPCR analysis was performed to study the genes related to CD8+ naïve T cell differentiation and proliferation. Cytokine profile and T-bet expression were analysed by qPCR and flow cytometry analysis.
Activated CTLs uptake TDEs in a time-dependent manner. TDEs reduced cellular proliferation of activated CTLs and blocked effector differentiation. Cytotoxic properties of CTLs were attenuated post uptake of TDE. The later was found to alter T-bet expression in the CD8+ T cells.
TDEs modulate CD8+T cell proliferation and differentiation in the tumor micro-environment. They also reduce the cytotoxic properties of CD8+T lymphocytes. TDE-mediated dysfunction of CTLs in the tumor microenvironment leads to proliferation of breast cancer cells.
Clinical trial identification
Legal entity responsible for the study
Arindam Bhattacharyya, Professor, Department of Zoology, University of Calcutta.
Has not received any funding.
All authors have declared no conflicts of interest.