The P2X7 Receptor in Tumor Immunity.

Fabio Grassi,Benedetta De Ponte Conti

doi:10.3389/fcell.2021.694831

Abstract

Extracellular adenosine triphosphate (eATP) is a potent mediator of the immune response via stimulation of purinergic P2 receptors. ATP concentration in the extracellular space increases dramatically during tissue damage and eATP acts as a danger-associated molecular pattern (DAMP) to alert innate immune system cells for tissue repair. Similarly, eATP is present at hundreds of micromolar concentration in the tumor microenvironment (TME). However, its impact on antitumor immune response is still not well established, probably because of the complexity of the responses it induces in different cells constituting the TME. On one hand, ATP released by tumor cells concomitantly to cell death can contribute to immunogenic cell death (ICD) that is proinflammatory for the innate immune compartment and beneficial for tumor control, while on the other hand, eATP can foster immune-suppressive mechanisms within the TME, thus contributing to tumor progression and metastasis. It is well established that T-cell immunity is pivotal in limiting tumor growth and possibly eradicating neoplastic cells. T cells are limited though in their antitumor activity through different mechanisms, such as exhaustion, anergy, and senescence; the pathways resulting in these cellular outcomes are not clear. Here, we review the function of P2X7 receptor in conditioning T cell-dependent immunity against cancer.

Highlights

Extracellular adenosine triphosphate can transduce signal into virtually all cells through two types of plasma membrane receptors: ATP-gated ion channels termed P2X receptors (P2XRs) and G protein-coupled receptors, named P2Y receptors (P2YRs) (Burnstock, 2006)
In the tumor microenvironment (TME), P2X7R activity conditions the function of different cell subsets and can have opposite influences on the progression of the disease as a tumor-promoting or contrasting factor
Signaling by Extracellular adenosine triphosphate (eATP) is diffused in all tissues; it is difficult to find a cell type that is insensitive to eATP

Summary

INTRODUCTION

Extracellular adenosine triphosphate (eATP) can transduce signal into virtually all cells through two types of plasma membrane receptors: ATP-gated ion channels termed P2X receptors (P2XRs) and G protein-coupled receptors, named P2Y receptors (P2YRs) (Burnstock, 2006). Consistent with P2X7R-mediated innate immunosuppression, P2X7R was recently shown to be highly expressed in TAMs and its deficiency inhibited the “M2-like” polarization of TAMs via downregulation of STAT6 and IRF4 phosphorylation both in vivo and in vitro (Qin et al, 2020) (Figure 1B) These results show that P2X7R activity can condition functionally different cells of the innate immune system in the TME with opposite outcomes on tumor growth control. P2X7R stimulation in tumor-specific T cells within the TME resulted in stress-induced cellular senescence that limited the expansion of tumoricidal cells This mechanism was dependent on mitochondrial reactive oxygen species (ROS) generation and p38 MAPK-dependent upregulation of cyclin-dependent kinase inhibitor 1A (Cdkn1a, encoding for p21Waf 1/Cip1) (Romagnani et al, 2020) (Figure 1B). Targeting of P2X7R in effector TILs might provide a unique rejuvenating signal able to sustain the tumoricidal response (Romagnani et al, 2020)

CONCLUDING REMARKS

DATA AVAILABILITY STATEMENT