CD4+CD25+ regulatory T cells inhibit natural killer cell functions in a transforming growth factor–β–dependent manner

Abstract

Tumor growth promotes the expansion of CD4+CD25+ regulatory T (T reg) cells that counteract T cell–mediated immune responses. An inverse correlation between natural killer (NK) cell activation and T reg cell expansion in tumor-bearing patients, shown here, prompted us to address the role of T reg cells in controlling innate antitumor immunity. Our experiments indicate that human T reg cells expressed membrane-bound transforming growth factor (TGF)–β, which directly inhibited NK cell effector functions and down-regulated NKG2D receptors on the NK cell surface. Adoptive transfer of wild-type T reg cells but not TGF-β −/− T reg cells into nude mice suppressed NK cell–mediated cytotoxicity, reduced NKG2D receptor expression, and accelerated the growth of tumors that are normally controlled by NK cells. Conversely, the depletion of mouse T reg cells exacerbated NK cell proliferation and cytotoxicity in vivo. Human NK cell–mediated tumor recognition could also be restored by depletion of T reg cells from tumor-infiltrating lymphocytes. These findings support a role for T reg cells in blunting the NK cell arm of the innate immune system.

PD-L1 blockade enhances anti-tumor efficacy of NK cells

“…TGFβ has been shown to downregulate CD16 expression on NK cells and lead to their conversion to a more immunoregulatory-like phenotype. 30,31 Tregs also sequester IL-2 which results in a decrease of NK cell survival. 31,32 Tregs and/or PD-1 engagement of T cells may also inhibit beneficial T cell/NK cell crosstalk that can potentially provide NK cells with IL2 or other stimulatory signals.…”

“…30,31 Tregs also sequester IL-2 which results in a decrease of NK cell survival. 31,32 Tregs and/or PD-1 engagement of T cells may also inhibit beneficial T cell/NK cell crosstalk that can potentially provide NK cells with IL2 or other stimulatory signals. Thus, blocking PD-L1 to mitigate induction of Treg expansion and the associated immunosuppression should lead to improved NK cell function and persistence.…”

Immune-based mechanisms of cytotoxic chemotherapy: implications for the design of novel and rationale-based combined treatments against cancer

“…36 Most platinum-based compounds inhibit STAT6-regulated expression of programmed death ligand-2, thus limiting immunosuppression by both DCs and tumor cells. 74 Low-dose CTX selectively, but transiently, suppresses Tregs 43,75,76 and impairs the production of immune-suppressive cytokines, such as IL-4, IL-10 and IL-13. 41,77 A prolonged and more effective Treg inhibition was achieved by metronomic CTX regimens in patients with advanced solid tumors 6 or with metastatic breast cancer.…”

Shaping of NK Cell Responses by the Tumor Microenvironment

“…Tregs were shown to control the homeostatic proliferation of NK cells and their anti-tumor immune responses [96]. Active recruitment and in situ proliferation contribute to the accumulation of Tregs in the tumor [97]. TGF-β is an important immunosuppressive factor produced by tumor and immune cells with broad effects on tumor-infiltrating immune cells [98].…”

“…It can also indirectly influence NK cell responses by affecting DC function, by inducing Tregs or by modulating the expression of adhesion molecules on endothelial cells in tumor vessels. Within the tumor microenvironment, TGF-β exerts its function mainly by its membrane-bound form presented by Tregs and MDSCs [95,97].…”