Tumor-associated macrophages promote intratumoral conversion of conventional CD4(+) T cells into regulatory T cells via PD-1 signalling

While regulatory T cells (T(regs)) and macrophages have been recognized as key orchestrators of cancer-associated immunosuppression, their cellular crosstalk within tumors has been poorly characterized. Here, using spontaneous models for breast cancer, we demonstrate that tumor-associated macrophages (TAMs) contribute to the intratumoral accumulation of T(regs) by promoting the conversion of conventional CD4(+) T cells (T(convs)) into T(regs). Mechanistically, two processes were identified that independently contribute to this process. While TAM-derived TGF-β directly promotes the conversion of CD4(+) T(convs) into T(regs) in vitro, we additionally show that TAMs enhance PD-1 expression on CD4(+) T cells. This indirectly contributes to the intratumoral accumulation of T(regs), as loss of PD-1 on CD4(+) T(convs) abrogates intratumoral conversion of adoptively transferred CD4(+) T(convs) into T(regs). Combined, this study provides insights into the complex immune cell crosstalk between CD4(+) T cells and TAMs in the tumor microenvironment of breast cancer, and further highlights that therapeutic exploitation of macrophages may be an attractive immune intervention to limit the accumulation of T(regs) in breast tumors.