The transcription factor FOXA1 upregulates PYCR1-mediated autophagy to suppress antitumor immunity in lung adenocarcinoma

Background: Immunotherapy has emerged as an effective treatment for lung adenocarcinoma (LUAD) in recent years. However, the ability of Cancer cells to suppress antitumor immune responses through multiple mechanisms has become one of the major challenges for therapy. PYCR1 can reinforce the proliferation of LUAD cells, but the function of PYCR1 in LUAD against the tumor immune response has not been fully elucidated.

Methods: The clinical significance of PYCR1 in LUAD and the relationship between PYCR1 expression and CD8⁺ T cell infiltration were examined by bioinformatics analysis. The expression of PYCR1 and CD8 in LUAD clinical samples was analyzed by immunohistochemistry. The expression of PYCR1 in the LUAD cell model was detected by qPCR. Flow cytometry, Lactate Dehydrogenase kit, Calcein-AM/PI staining, and Transwell were employed to analyze the effect of PYCR1 on CD8⁺ T cell function. Western blot and immunofluorescence were utilized to probe into the effect of PYCR1 on Autophagy. The interaction between PYCR1 and FOXA1 was evaluated by dual-luciferase assay and ChIP assay. Finally, in vitro and in vivo rescue experiments were conducted to verify the role of the FOXA1/PSYR1 axis in the immune regulation of LUAD.

Results: PYCR1 was upregulated in LUAD and was linked with the dismal prognosis of patients. Knockdown of PYCR1 in LUAD remarkably enhanced the activity of peripheral CD8⁺ T cells and facilitated the death of LUAD cells. In addition, overexpression of PYCR1 activated Autophagy in Cancer cells and dampened the anti-tumor immune response of CD8⁺ T cells. FOXA1 was an upstream transcriptional activator of PYCR1. Knockdown of FOXA1 potentiated the killing ability of CD8⁺ T cells on LUAD cells by repressing Autophagy, while overexpression of PYCR1 reversed the effect of FOXA1 knockdown, which was verified in mouse experiments.

Conclusion: FOXA1 upregulates PYCR1 expression, activates Autophagy in LUAD cells, and dampens CD8⁺ T cell antitumor immune response. Targeting FOXA1/PYCR1 may be a potential approach to improve LUAD immunotherapy.

Autophagy; CD8+ T cells; FOXA1; Lung adenocarcinoma; PYCR1.