Abstract
γδT cells have been reported to exert immunosuppressive functions in multiple solid malignant diseases, but their immunosuppressive functional subpopulation in breast cancer (BC) is still undetermined. Here, we collected 40 paired BC and normal tissue samples from Chinese patients for analysis. First, we showed that γδT1 cells comprise the majority of CD3+ T cells in BC; next, we found that CD73+γδT1 cells were the predominant regulatory T-cell (Treg) population in BC, and that their prevalence in peripheral blood was also related to tumour burden. In addition, CD73+γδT1 cells exert an immunosuppressive effect via adenosine generation. We also found that BC could modulate CD73 expression on γδT cells in a non-contact manner. The microarray analysis and functional experiments indicated that breast tumour cell-derived exosomes (TDEs) could transmit lncRNA SNHG16, which upregulates CD73 expression, to Vδ1 T cells. Regarding the mechanism, SNHG16 served as a ceRNA by sponging miR-16–5p, which led to the derepression of its target gene SMAD5 and resulted in potentiation of the TGF-β1/SMAD5 pathway to upregulate CD73 expression in Vδ1 T cells. Our results showed that the BC-derived exosomal SNHG16/miR-16–5p/SMAD5-regulatory axis potentiates TGF-β1/SMAD5 pathway activation, thus inducing CD73 expression in Vδ1 T cells. Our results first identify the significance of CD73+Vδ1 Tregs in BC, and therapy targeting this subpopulation or blocking TDEs might have potential for BC treatment in the future.
Highlights
Breast cancer (BC) is recognised as a “cold” tumour compared with other solid malignant diseases with strong immunogenicity, such as melanoma, lung cancer and colorectal cancer, scientists still focus on immune therapy and the immune microenvironment of breast cancer (BC), and the immune ecosystem within BC has been better elucidated recently with the advent of single-cell RNA-seq analysis[1] and mass cytometry technology.[2]
We aimed to explore whether there is a specific subtype of Vδ1+ T cells in BC that plays a major immunosuppressive role by evaluating the expression of regulatory immune cell markers (CD27, CD25, CD39, CD73, CTLA-4, CD122 and FoxP3) on Vδ1/2+ T cells isolated from PBHDs and Vδ1/2+ T cells isolated from peripheral blood of breast cancer patients (PBBCs), normal breast tissues (NT) and breast cancer (BC) tissues (Fig. 2a–d, Supplementary Fig. S3)
Our results indicated that the levels of p-SMAD5 and CD73 could not be modulated by tumour cell-derived exosomes (TDEs) alone, but when combined with TGF-β1, the TDEs increased the levels of p-SMAD5 and CD73, and this effect could be suppressed by SB-431542 but not dorsomorphin (Supplementary Fig. S7e, f)
Summary
Breast cancer (BC) is recognised as a “cold” tumour compared with other solid malignant diseases with strong immunogenicity, such as melanoma, lung cancer and colorectal cancer, scientists still focus on immune therapy and the immune microenvironment of BC, and the immune ecosystem within BC has been better elucidated recently with the advent of single-cell RNA-seq analysis[1] and mass cytometry technology.[2] Researchers have found that some immune subpopulations are highly associated with prognosis and have the potential to be therapeutic targets Among these subpopulations, γδT cells have been reported as a major component of tumour-infiltrating lymphocytes (TILs) in BC and are strongly correlated with unfavourable pathological characteristics and poor prognosis.[3] Wang and Peng et al.[3,4] first determined that γδT1 cells but not γδT2 cells were recruited from peripheral blood via the CXCR3/IP10 axis, were the dominant cell type in the CD3+ T-cell subsets in breast TILs, and functioned as regulatory immune cells via a unique TLR8 signalling pathway. Solid evidence has been presented that infiltrating γδT cells play a negative role in BC, and considering the crucial role of γδT cells in the innate and adaptive immune systems, it is rational to determine a specific marker for the identification of regulatory infiltrating γδT cells in BC
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