Citations 2
Regulatory T-cell Sensing of Extracellular ATP via P2RX7 Promotes Their Accumulation and Suppression and Drives Lung Tumor Growth
Santiago-Carvalho, Igor , Francisco, Ronaldo da Silva , Macedo, Bruna de Gois , Salgado, Caio Loureiro , Stoll, Carly R. , Shao, Samantha C. , Beniwal, Angad , Kwok, Tina , Banuelos, Alma , Cione, Marcos Pinheiro , White, Emily , Johnston, Tyler, Leff, Chloe , Silva-Junior, Ildefonso , Souza, Fabio Carvalho de, Thant, Win , Fernandez-Bussy, Sebastian, Abia-Trujillo, David, Vu, Linh H, Husta, Bryan C, Copland, John A. , Gounari, Fotini , Justilien, Verline , Cione, Marcos Vinícios Pinheiro , Francisco, Ronaldo , Macedo, Bruna Gois , Johnston, Tyler M , Leff, Chloe Liliana , Carvalho de Souza, Fabio , Pandya, Prita , D'Império Lima, Maria Regina , Fernandez-Bussy, Sebastian , Abia-Trujillo, David , Vu, Linh H , Tran, Nhan L , Husta, Bryan C , Copland, John A , Gounari, Fotini , Justilien, Verline , Lancaster, Jessica N , Borges da Silva, Henrique , Silva, Ildefonso , Pandya, Prita , Lima, Maria Regina D’Império , Tran, Nhan L. , Lancaster, Jessica N. , Silva, Henrique Borges da
Cancer Immunology Research | January 21, 2026 | Volume: 14 | Issue: 4 | Pages: 658-675
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.
Sensing of extracellular ATP via P2RX7 drives lung tumor growth through regulatory T cell suppressive function
Francisco, Ronaldo, Stoll, Carly R. , Cione, Marcos Pinheiro , Johnston, Tyler , Leff, Chloe , Souza, Fabio Carvalho de, Silva, Henrique Borges da , Santiago-Carvalho, Igor , de Gois Macedo, Bruna, Salgado, Caio Loureiro , Leff, Chloe Liliana, Junior, Ildefonso Silva, de Souza, Fabio Carvalho, Lancaster, Jessica N , da Silva, Henrique Borges, Borges da Silva, Henrique , Francisco, Ronaldo, Macedo, Bruna de Gois , White, Emily , Johnston, Tyler, Silva, Ildefonso , Souza, Fabio Carvalho de, Lima, Maria Regina D’Império , Lancaster, Jessica N.
No container title available | May 9, 2025 | Volume: No volume available | Issue: No issue available | Pages: No page available
ABSTRACT Lung cancer is the leading cause of cancer-related deaths worldwide and, despite treatment advances, immune suppression remains an obstacle to effective therapy. Effector CD4 + T cells (CD4 + Teffs) are critical for antitumor immunity, but their function is often inhibited by regulatory T cells (Tregs), which accumulate in lung tumors and perform 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. Here, we identify the extracellular ATP receptor P2RX7 as a key regulator of Treg function in lung tumors. Using a murine lung cancer model induced by Lewis lung carcinoma cells, we demonstrate that P2RX7 enhances the suppressive capacity of tumor-infiltrating Tregs, promoting tumor growth. In T cell-specific P2RX7-KO mice, reduced Treg infiltration was accompanied by increased CD4 + Teff accumulation and improved tumor control. Treg-specific P2RX7-KO mice exhibit reduced tumor growth, confirming a cell-intrinsic role of P2RX7 in Tregs. Suppression assays revealed that tumor-infiltrating WT Tregs have greater suppressive activity compared to P2RX7-KO Tregs, which failed to inhibit type 1 and Tfh-like responses. This was associated with increased tumor-specific IgG production by lung B cells in P2RX7-KO mice. We also observed that WT Tregs express higher levels of the immunosuppressive surface molecule CTLA-4 when compared to P2RX7-KO Tregs. In summary, we show that P2RX7 expression on Tregs is essential for their suppressive function in lung cancer, and targeting of P2RX7 may constitute a novel strategy to improve lung cancer treatment by alleviating Treg-mediated immune suppression.