P2RX7: a double-edged sword in tumor immunotherapy

Abstract

Expression of the purinergic receptor P2RX7 by CD8+ T cells promotes generation of memory populations following acute infections, but recent studies have indicated that P2RX7 may limit the efficacy of anti-tumor responses. We show that P2RX7 is beneficial for optimal melanoma control in a mouse CD8+ T cell adoptive transfer model. Tumor specific P2rx7-/- CD8+ T cells exhibited impaired mitochondrial maintenance and function but did not display signs of overt exhaustion early in the anti-tumor response. However, as the tumor burden increased, the relative frequency of P2RX7 deficient CD8+ T cells declined within the tumor, correlating with reduced proliferation, increased apoptosis and mitochondrial dysfunction. Extending these studies, we found that transient in vitro stimulation of P2RX7 using the ATP analog BzATP led to enhanced B16 tumor control by CD8+ T cells which was dependent on sustained P2RX7 signaling within the tumor. We also demonstrate that P2RX7+ CD8+ T cells are vulnerable to NAD+- induced cell death (NICD) by ADP-ribosylation of P2RX7. Tumor cells express the ADPribosyltransferase ART1 which induces NICD in P2RX7+ CD8+ T cells. We found that ART1 deficient B16 tumors were more susceptible to CD8+ T cell adoptive cell therapy. Furthermore, we found that loss of ART1 on B16 tumors allowed for P2RX7+ CD8+ T cells to persist within the tumor microenvironment. These findings are consistent with the concept that extracellular ATP (eATP) sensing by P2RX7 on CD8+ T cells is required for their ability to efficiently eliminate tumors by promoting mitochondrial fitness and highlights the potential for P2RX7 stimulation, potentially combined with ART1 blockade, as a novel therapeutic treatment to enhance tumor immunotherapy.