Data from Regulatory T-cell Sensing of Extracellular ATP via P2RX7 Promotes Their Accumulation and Suppression and Drives Lung Tumor Growth
Year: 2026
Type: other
Abstract: Lung cancer is the leading cause of cancer-related deaths worldwide, and despite advances in treatment, immune suppression remains an obstacle to effective therapy. Effector CD4+ T cells (CD4+ Teff) are critical for antitumor immunity, but their function is often inhibited by regulatory T cells (Treg), which accumulate in lung tumors and mediate suppressive functions through multiple mechanisms. This suppression leads to tumor progression and poor patient outcomes. However, the mechanisms underlying Treg-mediated suppression are not fully understood. Herein, we identify the extracellular adenosine 5-triphosphate receptor P2RX7 as a key regulator of Treg function in lung tumors. In a murine lung cancer model induced by Lewis lung carcinoma cells, we found that P2RX7 enhanced the suppressive capacity of tumor-infiltrating Tregs, promoting tumor growth. In T cell–specific P2RX7-knockout (P2RX7-KO) mice, reduced Treg infiltration was accompanied by increased CD4+ Teff accumulation and improved tumor control. Treg-specific P2RX7-KO mice exhibited reduced tumor growth, confirming a Treg-intrinsic role of P2RX7. Suppression assays revealed that tumor-infiltrating wild-type Tregs had greater suppressive activity compared with P2RX7-KO Tregs, which failed to inhibit type 1 and follicular helper T–like responses. This was associated with increased tumor-specific IgG production by lung B cells in P2RX7-KO mice. We also observed that wild-type Tregs expressed higher levels of the immunosuppressive molecule CTLA-4 when compared with P2RX7-KO Tregs. Thus, we conclude that P2RX7 expression on Tregs is essential for their suppressive function in lung cancer and targeting P2RX7 may constitute a strategy to improve lung cancer treatment by alleviating Treg-mediated immune suppression.
Authors: Igor Santiago-Carvalho, Ronaldo Francisco, Bruna Gois Macedo, Caio Loureiro Salgado, Carly R. Stoll, Samantha Shao, Angad Beniwal, Tina Kwok, Alma Banuelos, Marcos Pinheiro Cione, Emily White, Tyler M. Johnston, Chloe Liliana Leff, Ildefonso Silva Junior, Fabio Carvalho de Souza, Win Thant, Prita Pandya, Maria Regina D’Império Lima, Sebastian Fernandez-Bussy, David Abia-Trujillo, Linh H. Vu, Nhan L. Tran, Bryan C. Husta, John A. Copland, Fotini Gounari, Verline Justilien, Jessica Naomi Lancaster, Henrique Borges da Silva
Language: English
Subfield: Physiology
Domain: Life Sciences
Open Access status: gold
OpenAlex ID: W7147179004