Santiago-Carvalho et al. identified the extracellular ATP sensor P2RX7 as a poor prognostic factor in NSCLC that was highly enriched in Tregs. In mouse models, Treg-specific KO of P2RX7 reduced lung tumor burden, without altering Treg numbers. However, infiltrating Tregs exhibited impaired effector suppression ex vivo, with lower activation and CTLA-4 expression. Among effectors, P2RX7 KO enhanced the i.t. abundance of CD4+ cells, particularly Tfh, along with GC B cells and TLSs. In vitro, agonism of P2RX7 increased calcium flux, suggesting an impact on Treg activation. Pharmacological inhibition of P2RX7 reduced tumor Tregs and modestly reduced lung tumor burden.
Contributed by Morgan Janes
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+ Teffs) are critical for antitumor immunity, but their function is often inhibited by regulatory T cells (Tregs), 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 ATP 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-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 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 wild-type Tregs expressed higher levels of the immunosuppressive molecule CTLA-4 when compared to P2RX7-KO Tregs. Thus, we conclude that P2RX7 expression on Tregs is essential for their suppressive function in lung cancer and targeting of P2RX7 may constitute a strategy to improve lung cancer treatment by alleviating Treg-mediated immune suppression.
Author Info: (1) Mayo Clinic Phoenix, Arizona United States. ROR: https://ror.org/02qp3tb03 (2) Brigham and Women's Hospital Boston, Massachusetts United States. ROR: https://ror.org/04b6nzv94
Author Info: (1) Mayo Clinic Phoenix, Arizona United States. ROR: https://ror.org/02qp3tb03 (2) Brigham and Women's Hospital Boston, Massachusetts United States. ROR: https://ror.org/04b6nzv94 (3) Mayo Clinic Scottsdale, Arizona United States. ROR: https://ror.org/02qp3tb03 (4) Mayo Clinic Phoenix, Arizona United States. ROR: https://ror.org/02qp3tb03 (5) Mayo Clinic Phoenix, Arizona United States. ROR: https://ror.org/02qp3tb03 (6) Mayo Clinic Phoenix, Arizona United States. ROR: https://ror.org/02qp3tb03 (7) Mayo Clinic Phoenix, Arizona United States. ROR: https://ror.org/02qp3tb03 (8) Mayo Clinic Phoenix, Arizona United States. ROR: https://ror.org/02qp3tb03 (9) Mayo Clinic Scottsdale, Arizona United States. ROR: https://ror.org/02qp3tb03 (10) Mayo Clinic Phoenix, Arizona United States. ROR: https://ror.org/02qp3tb03 (11) Mayo Clinic Phoenix, Arizona United States. ROR: https://ror.org/02qp3tb03 (12) Mayo Clinic Phoenix, Arizona United States. ROR: https://ror.org/02qp3tb03 (13) Mayo Clinic Phoenix, Arizona United States. ROR: https://ror.org/02qp3tb03 (14) Mayo Clinic Phoenix, Arizona United States. ROR: https://ror.org/03jp40720 (15) Mayo Clinic Phoenix, Arizona United States. ROR: https://ror.org/02qp3tb03 (16) Massachusetts General Hospital Boston United States. ROR: https://ror.org/002pd6e78 (17) Mayo Clinic Jacksonville, Florida United States. ROR: https://ror.org/03zzw1w08 (18) Universidade de So Paulo Sao Paulo, Sao Paulo Brazil. ROR: https://ror.org/036rp1748 (19) Mayo Clinic Jacksonville, FL United States. ROR: https://ror.org/03zzw1w08 (20) Mayo Clinic Jacksonville, Florida United States. ROR: https://ror.org/03zzw1w08 (21) Mayo Clinic United States. ROR: https://ror.org/03zzw1w08 (22) Mayo Clinic Scottsdale, AZ United States. ROR: https://ror.org/03jp40720 (23) Mayo Clinic Jacksonville, Florida United States. ROR: https://ror.org/03zzw1w08 (24) Mayo Clinic Jacksonville, FL United States. ROR: https://ror.org/02qp3tb03 (25) Mayo Clinic Phoenix, Arizona United States. ROR: https://ror.org/02qp3tb03 (26) Mayo Clinic Jacksonville, Florida United States. ROR: https://ror.org/02qp3tb03 (27) Mayo Clinic Phoenix, Arizona United States. ROR: https://ror.org/02qp3tb03 (28) Mayo Clinic Phoenix, Arizona United States. ROR: https://ror.org/02qp3tb03
