TY - JOUR
T1 - P2RX7 Enhances Tumor Control by CD8+T Cells in Adoptive Cell Therapy
AU - Wanhainen, Kelsey M.
AU - Peng, Changwei
AU - Zhou, Maggie H.
AU - De Gois MacEdo, Bruna
AU - O'Flanagan, Stephen
AU - Yang, Tingyuan
AU - Kelekar, Ameeta
AU - Burbach, Brandon J.
AU - Da Silva, Henrique Borges
AU - Jameson, Stephen C.
N1 - Publisher Copyright:
© 2022 American Association for Cancer Research.
PY - 2022/7
Y1 - 2022/7
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=85133980539&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85133980539&partnerID=8YFLogxK
U2 - 10.1158/2326-6066.CIR-21-0691
DO - 10.1158/2326-6066.CIR-21-0691
M3 - Article
C2 - 35588154
AN - SCOPUS:85133980539
SN - 2326-6066
VL - 10
SP - 871
EP - 884
JO - Cancer Immunology Research
JF - Cancer Immunology Research
IS - 7
ER -