Programmed cell death-1 receptor-mediated regulation of Tbet ⁺ NK1.1 ⁻ innate lymphoid cells within the tumor microenvironment

Abstract

Innate lymphoid cells (ILCs) play a key role in tissue-mediated immunity and can be controlled by coreceptor signaling. Here, we define a subset of ILCs that are Tbet + NK1.1 − and are present within the tumor microenvironment (TME). We show programmed death-1 receptor (PD-1) expression on ILCs within TME is found in Tbet + NK1.1 − ILCs. PD-1 significantly controlled the proliferation and function of Tbet + NK1.1 − ILCs in multiple murine and human tumors. We found tumor-derived lactate enhanced PD-1 expression on Tbet + NK1.1 − ILCs within the TME, which resulted in dampened the mammalian target of rapamycin (mTOR) signaling along with increased fatty acid uptake. In line with these metabolic changes, PD-1-deficient Tbet + NK1.1 − ILCs expressed significantly increased IFNγ and granzyme B and K. Furthermore, PD-1-deficient Tbet + NK1.1 − ILCs contributed toward diminished tumor growth in an experimental murine model of melanoma. These data demonstrate that PD-1 can regulate antitumor responses of Tbet + NK1.1 − ILCs within the TME.

Innate lymphoid cells and tumor-derived lactic acid: novel contenders in an enduring game

“…Nevertheless, tumor-derived lactate has been found to enhance the expression of PD1 on a subset of ILCs that are T-bet + NK1.1 − within the tumor microenvironment ( Figure 1 ), which led to diminished signaling of mammalian target of rapamycin (mTOR) together with elevated uptake of fatty acids. Consistent with the metabolic alterations, PD1-deficient T-bet + NK1.1 − ILCs have been characterized by an increased expression of IFN-γ and granzyme B and K. In addition, the presence of PD1-deficient T-bet + NK1.1 − ILCs has been associated with inhibited growth of melanomas in mice ( 45 ). Although further studies are necessary to fully understand the impact of tumor-derived lactate on ILCs, these findings pave the way for exploring strategies aimed at regulating the lactate levels within the tumor microenvironment.…”

PD‐1: A critical player and target for immune normalization

“…In certain cancers such as pancreatic cancer, breast cancer and gastrointestinal tumour, these malignancies infiltrate various ILC subsets, including ILC2s, Tbet + NK1.1 À and ILC3. The expression of PD-1 in ILCs increases, thereby promoting tumour development [66,67]. When PD-1 is absent, ILC2 metabolism shifts towards glycolysis, glutamine breakdown, and methionine catabolism.…”

Crosstalk between metabolism and cell death in tumorigenesis

“…Secondly, lactate represses T cell by modulating the expression of immune checkpoint molecules PD-1 and PD-L1, which causes immune escape. Lactate restrains PD-1 expression on effector T cells to suppress T cell cytotoxicity, which causes immune escape and even affects the effectiveness of tumor immunotherapy [236][237][238]. Lactate in the tumor microenvironment also acts as an upstream molecule for the transcription factor NF-κB, and synergistically affect tumor angiogenesis [239].…”