Breast cancer stem cells generate immune-suppressive T regulatory cells by secreting TGF to evade immune-elimination

Cancer stem cells (CSCs), being the primary contributors in tumor initiation, metastasis, and relapse, ought to have seminal roles in evasion of immune surveillance. Tumor-promoting CD4(+)CD25(+)FOXP3(+)T-regulatory cells (Tregs) have been described to abolish host defense mechanisms by impeding the activities of other immune cells including effector T cells. However, whether CSCs can convert effector T cells to immune-suppressive Treg subset, and if yes, the mechanism underlying CSC-induced Treg generation, are limitedly studied. In this regard, we observed a positive correlation between breast CSC and Treg signature markers in both in-silico and immunohistochemical analyses. Mirroring the conditions during tumor initiation, low number of CSCs could successfully generate CD4(+)CD25(+)FOXP3(+) Treg cells from infiltrating CD4(+) T lymphocytes in a contact-independent manner. Suppressing the proliferation potential as well as IFN gamma production capacity of effector T cells, these Treg cells might be inhibiting antitumor immunity, thereby hindering immune-elimination of CSCs during tumor initiation. Furthermore, unlike non-stem cancer cells (NSCCs), CSCs escaped doxorubicin-induced apoptosis, thus constituting major surviving population after three rounds of chemotherapy. These drug-survived CSCs were also able to generate CD4(+)CD25(+)FOXP3(+) Treg cells. Our search for the underlying mechanism further unveiled the role of CSC-shed immune-suppressive cytokine TGF beta, which was further increased by chemotherapy, in generating tumor Treg cells. In conclusion, during initiation as well as after chemotherapy, when NSCCs are not present in the tumor microenvironment, CSCs, albeit present in low numbers, generate immunosuppressive CD4(+)CD25(+)FOXP3(+) Treg cells in a contact-independent manner by shedding high levels of immune-suppressive Treg-polarizing cytokine TGF beta, thus escaping immune-elimination and initiating the tumor or causing tumor relapse.