Dataset Information

Norepinephrine inhibits CD8+ T cell infiltration and function, inducing anti-PD-1 mAb resistance in lung adenocarcinoma

ABSTRACT: BACKGROUND:Mental stress-induced neurotransmitters can affect the immune system in various ways, leading to tumor immune escape. Therefore, a better understanding of the potential functions of neurotransmitters in the tumor immune microenvironment is expected to promote the development of novel anti-tumor therapies, while facilitating synergistic immune therapy. METHODS: In this study, we analyzed the plasma levels of neurotransmitters in anti-programmed cell death protein 1 (PD-1) monoclonal antibody (mAb)-resistance patients and sensitive patients, to identify significantly different neurotransmitters. Subsequently, animal experiments, transcriptome analysis, metabolomic analysis, and experiments in vitro were used to reveal the specific mechanism of norepinephrine’s (NE) effect on immunotherapy. RESULTS: The plasma NE levels were higher in anti-PD-1 mAb-resistance patients, which may be the main cause of anti-PD-1 mAb resistance. An animal model was established for verification, which further demonstrated that NE could cause anti-PD-1 mAb resistance. Then, from the perspective of the immunosuppressive microenvironment to explore the specific mechanism of NE-induced anti-PD-1 mAb resistance, we found that NE can affect the secretion of the C-X-C Motif Chemokine Ligand 9 (CXCL9) and the immunosuppressive metabolite adenosine (ADO) in tumor cells, thereby inhibiting chemotaxis and function of CD8+ T cells. Notably, the WNT7A/β-catenin signaling pathway plays a crucial role in the NE-induced decrease in the secretion of CXCL9 and disturbance of ADO metabolism. CONCLUSION: NE can affect the secretion of CXCL9 and ADO in tumor cells, thereby inhibiting chemotaxis and the function of CD8+ T cells and inducing anti-PD-1 mAb resistance in lung adenocarcinoma (LUAD).

ORGANISM(S): Homo sapiens

PROVIDER: GSE218402 | GEO | 2023/04/04

REPOSITORIES: GEO

ACCESS DATA

Dataset's files

Source:

			Action	DRS
		Other

Items per page:

1 - 1 of 1

Similar Datasets

Project description:Using both global and conditional knockout mice, we demonstrated that the transcription factor Basic Helix-Loop-Helix Family Member E40 (BHLHE40/DEC1) is required in T cells for rejection of mouse syngeneic tumors upon immune checkpoint therapy (ICT) with anti-PD-1 or anti-CTLA-4 monoclonal antibody (mAb) treatment. Using single cell RNA sequencing (scRNAseq) we profiled intratumoral CD45+ cells from syngeneic mouse sarcomas that (a) grow progressively with control treatment in either Bhlhe40+/+ or Bhlhe40-/- tumor-bearing mice, (b) reject following anti-PD-1 or anti-CTLA-4 ICT in Bhlhe40+/+ tumor-bearing mice, or (c) grow progressively following anti-PD-1 or anti-CTLA-4 in Bhlhe40-/- mice. We performed two separate scRNAseq experiments with the same conditions but harvested tumors on either day 9 post-tumor transplant or day 11 post-tumor transplant. The groups were as follows: (1) Control mAb Bhlhe40+/+, (2) Control mAb Bhlhe40-/-, (3) anti-PD-1 Bhlhe40+/+, (4) anti-PD-1 Bhlhe40-/-, (5) anti-CTLA-4 Bhlhe40+/+, and (6) anti-CTLA-4 Bhlhe40-/-. scRNAseq of intratumoral immune cells in BHLHE40-deficient mice revealed differential ICT-induced immune cell remodeling. These BHLHE40-dependent gene expression alterations were associated with altered metabolism, NF-kB signaling, and IFN- response in subpopulations of intratumoral CD4+ and CD8+ T cells. Intratumoral T cells from tumor-bearing Bhlhe40-/- mice also had higher transcript expression of the inhibitory receptor gene Tigit, along with altered transcript expression of chemokine/chemokine receptor granzyme family members. Bhlhe40-/- CD4+ and CD8+ T cells also had reduced ICT-driven IFN- production. Furthermore, BHLHE40 was required for ICT-induced remodeling of macrophages from a CX3CR1+ CD206+ subpopulation to an iNOS+ subpopulation. While anti-PD-1 or anti-CTLA-4 ICT in tumor-bearing Bhlhe40-/- mice led to tumor outgrowth—several BHLHE40-dependent changes were specific to the ICT treatment that was administered.

Dataset Information

Norepinephrine inhibits CD8+ T cell infiltration and function, inducing anti-PD-1 mAb resistance in lung adenocarcinoma

Dataset's files

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets