CTLA-4 blockade antibody enhances effector T cell function and mediates intratumoral Treg cell depletion to induce durable antitumor immune responses and tumor regression. However, the responsiveness of CTLA-4 blockade therapy remains low clinically and severe immunotherapy-related adverse effects are associated with CTLA-4 monotherapy.
Lactate accumulation has been regarded as a marker of metabolically abnormal tumor microenvironment, which exhibits important regulatory role in the maintenance of tumor-infiltrating Treg cell function. It has been demonstrated that lactate is involved in the regulation of the PD-1 monotherapy efficacy, whether it modulates CTLA-4 expression in Treg cells to affect the CTLA-4 blockade therapyresponses is worth exploring.
The research team constructed murine tumor models to address whetherlactate uptakeby Treg cells affects CTLA-4 blockade therapy.Tumor bearing mice with Treg cellconditional knockout ofSlc16a1, which encodes lactate transporter MCT1, cannot respond to CTLA-4 blockade therapy. Mechanistically, lactate uptake by Treg cells increased Foxp3 expression. And then Foxp3 promoted the transcription ofUsp39, a component of RNA splicing machinery, thereby sustaining USP39-mediated RNA splicing to facilitate CTLA-4 expression, which in turn contributes to the efficacy of CTLA-4 blockade. Moreover, the efficiency of CTLA-4 RNA splicing was increased in tumor-infiltrating Treg cells from patients with colorectal cancer. These findings highlight USP39 as a lactate sensor for Treg cell environmental adaptation and identify a mechanistic connection between lactate and RNA splicing in Treg cells, with therapeutic implications for antitumor immunity.
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Ph.D student Rui Ding, associateresearchfellow Xiaoyan Yu of Shanghai Institute of Immunology, SJTUSM,and Professor Zhilin Hu of Nanjing Medical University are the co-first authors of this paper. PI Qiang Zou and Youqiong Ye of Shanghai Institute of Immunology, SJTUSM, Professor Ren Zhao of Ruijin hospital, SJTUSM and Professor Zhi-yu Ni of Hebei University of Engineering are the co-corresponding authors of this paper.