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Purpose <p>The potent antitumor effects of interleukin 12 (IL12) gene therapy in glioblastoma (GBM) are significantly attenuated by the highly immunosuppressive microenvironment and the upregulation of the PD-1/PD-L1 immune checkpoint. However, combining IL12 gene therapy with PD-1/PD-L1 inhibitors failed to improve efficacy. This study aims to assess the effects of silencing the immunosuppressive long noncoding RNA <i>INCR1</i> when combined with IL12 therapy.</p> Methods <p>RNAscope in situ hybridization was performed to analyze <i>INCR1</i> and <i>PD-L1</i> expression in tumor tissues from GBM patients pre- and post-IL12 gene therapy. Quantitative PCR was used to analyze immunosuppressive gene expression in patient-derived GBM cells co-cultured with immune cells stimulated with IL12. The effects of <i>INCR1</i> and <i>PD-L1</i> silencing on the expression of immunosuppressive genes were evaluated by RNA sequencing. 3D-cytotoxicity assays were performed to assess the activity of immune cells against GBM tumor cells.</p> Results <p><i>INCR1</i> and <i>PD-L1</i> expression was upregulated in tumor tissue from GBM patients treated with IL12 gene therapy compared to the tumor tissue of the same patients before the IL12 treatment. Co-culture of patient-derived GBM cells with IL12-stimulated immune cells increased the expression of several immunosuppressive genes. Knocking down <i>INCR1</i> was more effective than silencing <i>PD-L1</i> in reducing the expression of multiple immunosuppressive genes. <i>INCR1</i> silencing improved IL12-mediated immune cell antitumor activity compared to monoclonal antibodies targeting the PD-1/PD-L1 immune checkpoint signaling.</p> Conclusion <p><i>INCR1</i> silencing affects more immune evasive pathways than PD-L1. Targeting <i>INCR1</i> may represent a valid approach to improve the efficacy of IL12 therapy in GBM.</p>

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Improving IL12 immunotherapy in glioblastoma by targeting the long noncoding RNA INCR1

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年3月4日

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  • Shikha Saini,
  • Josephina A. M. A. Gadet,
  • Gordon J. Freeman,
  • E. Antonio Chiocca,
  • Marco Mineo

摘要

Purpose

The potent antitumor effects of interleukin 12 (IL12) gene therapy in glioblastoma (GBM) are significantly attenuated by the highly immunosuppressive microenvironment and the upregulation of the PD-1/PD-L1 immune checkpoint. However, combining IL12 gene therapy with PD-1/PD-L1 inhibitors failed to improve efficacy. This study aims to assess the effects of silencing the immunosuppressive long noncoding RNA INCR1 when combined with IL12 therapy.

Methods

RNAscope in situ hybridization was performed to analyze INCR1 and PD-L1 expression in tumor tissues from GBM patients pre- and post-IL12 gene therapy. Quantitative PCR was used to analyze immunosuppressive gene expression in patient-derived GBM cells co-cultured with immune cells stimulated with IL12. The effects of INCR1 and PD-L1 silencing on the expression of immunosuppressive genes were evaluated by RNA sequencing. 3D-cytotoxicity assays were performed to assess the activity of immune cells against GBM tumor cells.

Results

INCR1 and PD-L1 expression was upregulated in tumor tissue from GBM patients treated with IL12 gene therapy compared to the tumor tissue of the same patients before the IL12 treatment. Co-culture of patient-derived GBM cells with IL12-stimulated immune cells increased the expression of several immunosuppressive genes. Knocking down INCR1 was more effective than silencing PD-L1 in reducing the expression of multiple immunosuppressive genes. INCR1 silencing improved IL12-mediated immune cell antitumor activity compared to monoclonal antibodies targeting the PD-1/PD-L1 immune checkpoint signaling.

Conclusion

INCR1 silencing affects more immune evasive pathways than PD-L1. Targeting INCR1 may represent a valid approach to improve the efficacy of IL12 therapy in GBM.