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 co-receptor 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 mTOR signaling along with increased fatty acid uptake. In line with these metabolic changes, PD-1 deficient Tbet+NK1.1-ILCs expressed significantly increased IFNg, granzyme B and K. Furthermore, PD1 deficient Tbet+NK1.1- ILCs contributed towards diminished tumor growth in an experimental murine model of melanoma. These data demonstrate that PD-1 can regulate anti-tumor responses of Tbet+NK1.1-ILCs 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 − 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.…”

Twenty-One Flavors of Type 1 Innate Lymphoid Cells with PD-1 (Programmed Cell Death-1 Receptor) Sprinkles

“…Recently, our group has identified a previously undefined subset of T-bet + NK.1.1 − NKp46 – ILC1s that is regulated by PD1 in the TME in both murine and human cancers [ 92 ]. Tumor-derived lactate was shown to induce PD-1 within these subsets and PD1 signaling inhibited the proliferation of T-bet + ILC1s in the TME along with reducing IFN-γ production thereby promoting pro-tumor responses.…”

Exploring the role of m6A methylation regulators in glioblastoma multiforme and their impact on the tumor immune microenvironment

“…5 The temporal dimension is a crucial factor in the progression, drug resistance, and metastasis of tumors as evidenced by numerous studies. 6 A close correlation between the temporal dimension and the development and prognosis of glioblastoma (GBM) has also been established. 7,8 N6-methyladenosine (m6A) modification is a key RNA molecular modification in organisms, not only in mRNA but also in a variety of ncRNAs.…”

“…Within this intricate environment, various components coexist, including fibroblasts and tumor, glial, immune, inflammatory, and other activated tumor‐infiltrating immune cells, while microvasculature, extracellular matrix, and infiltrating biomolecules contribute to this complex milieu 5 . The temporal dimension is a crucial factor in the progression, drug resistance, and metastasis of tumors as evidenced by numerous studies 6 . A close correlation between the temporal dimension and the development and prognosis of glioblastoma (GBM) has also been established 7,8…”