P2RX7 Enhances Tumor Control by CD8+T Cells in Adoptive Cell Therapy

Kelsey M Wanhainen, Changwei Peng, Maggie H. Zhou, Bruna de Gois Macedo, Stephen D O'flanagan, Tingyuan Yang, Ameeta Kelekar, Brandon J. Burbach, Henrique Borges da Silva, Stephen C. Jameson

Research output: Contribution to journalArticlepeer-review

Abstract

Expression of the purinergic receptor P2RX7 by CD8+ T cells promotes the generation of memory populations following acute infections. However, data suggest that P2RX7 may limit the efficacy of antitumor responses. Herein, 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 antitumor response. However, as the tumor burden increased, the relative frequency of P2RX7-deficient CD8+ T cells declined within the tumor; this correlated with reduced proliferation, increased apoptosis, and mitochondrial dysfunction. Extending these studies, we found that the transient in vitro stimulation of P2RX7 using the ATP analogue BzATP led to enhanced B16 melanoma control by CD8+ T cells. These findings are in keeping 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 underscore the potential for P2RX7 stimulation as a novel therapeutic treatment to enhance tumor immunotherapy.

Original languageEnglish (US)
Pages (from-to)871-884
Number of pages14
JournalCancer Immunology Research
Volume10
Issue number7
DOIs
StatePublished - Jul 2022

Bibliographical note

Funding Information:
K.M. Wanhainen reports grants from NIH NCI during the conduct of the study. H. Borges da Silva reports grants from NIH (NIAID) and the Cancer Research Institute during the conduct of the study. S.C. Jameson reports grants

Funding Information:
This work was supported by the NIH (R01 AI145147 to S.C. Jameson; R00 AI139381 to H. Borges da Silva; F30 CA250231 to K.M. Wanhainen), and H. Borges da Silvawas supported by a Paul C. Shiverick/CRI Irvington fellowship. We thank Ananda Goldrath (UCSD) and Matthew Mescher (UMN) for providing us with the B16.gp33 and B16.OVA cell lines, respectively, and thank Peter Hinderlie and Jeffrey Miller (UMN) for their assistance with the IncuCyte assays. We appreciate all members of the Jamequist lab for input on these studies and critical comments on the manuscript.

Publisher Copyright:
© 2022 American Association for Cancer Research.

PubMed: MeSH publication types

  • Journal Article
  • Research Support, Non-U.S. Gov't
  • Research Support, N.I.H., Extramural

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