Abstract:
Objective: This study aimed to investigate the role of RGS2 in immune regulation and its impact on the efficacy of PD-1/PD-L1 blockade therapy in lung cancer (LC), as well as to explore the regulatory relationship between RGS2 and BATF2 in modulating T cell exhaustion and tumor immune evasion.
Methods: Single-cell transcriptome-based analysis identified CD8+ T-cell profiles as well as regulatory factors in six lung cancer patients receiving neoadjuvant PD-1 blockade therapy. Regulatory factors were validated in vivo via LLC cells and murine tumor organoid models in RGS2 knockout (RGS2-/-) and BATF2 knockout (BATF2-/-) mice. Functional assays evaluated metastasis, immune infiltration, and T-cell polarization. Mechanistic studies explored the transcriptional regulation of RGS2 by BATF2 using luciferase reporter assays, knockout and co-culture systems. Functional assays assessed metastasis, immune infiltration, and T cell polarization.
Results: RGS2 was highly expressed in CD8+ T-exhausted (Tex) cells and was associated with pro-inflammatory pathways, including TNF-a signaling via NF-κB. High RGS2 expression predicted poor clinical outcomes and limited response to PD-1/PD-L1 blockade therapy. In RGS2-/- mice, metastasis and angiogenesis were suppressed, CD8+ effector T cells were enhanced, and T cell exhaustion markers (PD-1, CTLA4, Galectin-9) were reduced. BATF2 was identified as a key transcriptional regulator of RGS2, promoting T cell exhaustion through inhibition of CXCL13 secretion. Knockdown of BATF2 or RGS2 impaired lung cancer cell proliferation, enhanced sensitivity to NK cell-mediated cytotoxicity, and reduced immune escape. In BATF2-/- mice, stem-like CD8+ T cells were increased, while exhausted T cells were reduced, leading to improved anti-tumor immune responses.
Conclusion: RGS2, regulated by BATF2, plays a critical role in promoting T cell exhaustion and tumor immune evasion in lung cancer. Targeting the BATF2-RGS2 axis may enhance the effectiveness of PD-1/PD-L1 blockade therapy by reversing T cell exhaustion and improving anti-tumor immunity. These findings provide a novel therapeutic strategy for enhancing immunotherapy outcomes in LC.
