BTN3A1 Drives Vγ9Vδ2 T Cell Exhaustion in Cervical Cancer

Jian Liu and the team aimed to investigate how BTN3A1 in cervical cancer promotes Vγ9Vδ2 T cell exhaustion. Vγ9Vδ2 T cells are crucial for cancer immunotherapy, but their efficacy is limited by exhaustion. BTN3A1, a molecule expressed on tumor cells, was suspected to play a role in this process by regulating transcription factors downstream of TCR signaling.

Tumor samples from patients with cervical cancer and cervical cancer cell line-derived xenograft mice were analyzed using flow cytometry to assess the exhausted phenotype of tumor-infiltrating Vγ9Vδ2 T cells.

The relationship between BTN3A1 expression and Vγ9Vδ2 T cells in cervical cancer, as well as their correlation with patient prognosis, was examined using data from The Cancer Genome Atlas (TCGA) database.

Cervical cancer cell lines with BTN3A1 knockout (KO) and overexpression (OE) were generated through lentiviral transduction and co-cultured with expanded Vγ9Vδ2 T cells. The function of these T cells was assessed through flow cytometry. RNA sequencing (RNA-seq), flow cytometry, Western blotting, and gene manipulation were used to identify the pathways and transcription factors (TFs) involved in BTN3A1-induced Vγ9Vδ2 T cell exhaustion and the factors regulating BTN3A1 expression.

The results demonstrated that BTN3A1 enhances exhaustion markers and reduces effector molecule secretion in Vγ9Vδ2 T cells. BTN3A1-induced exhaustion was mediated by NR4A2/3 upregulation and could be reversed by blocking TCR signaling. IFN-γ from Vγ9Vδ2 T cells promoted BTN3A1 and PD-L1 expression, creating an immunosuppressive feedback loop.

The study concluded that BTN3A1, through TCR binding and NR4A2/3 induction, contributes to Vγ9Vδ2 T cell exhaustion in cervical cancer, suggesting a potential target to improve immunotherapy outcomes.

This study was supported by the National Key Research and Development Program of China (No.2021YFC2701204 to H.W.), the National Natural Science Foundation of China (No.82373260 to H.W.), the “Jianbing” and “Lingyan” R&D programs of Zhejiang province (No.2022C03013 to H.W.).

Source: https://pubmed.ncbi.nlm.nih.gov/39342337/

Liu J, Wu M, Yang Y, et al. (2024). “BTN3A1 expressed in cervical cancer cells promotes Vγ9Vδ2 T cells exhaustion through upregulating transcription factors NR4A2/3 downstream of TCR signaling.” Cell Commun Signal. 2024;22(1):459. Published 2024 Sep 28. doi:10.1186/s12964-024-01834-0