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<p>Insulin-like growth factor-1 (IGF-1) is associated with prostate cancer (PCa) development and lethality and exhibits immunosuppressive properties in other models. We investigated IGF-1’s tumor-intrinsic immune effects in PCa to understand mechanisms underlying its poor immunotherapy response. Transcriptional profiling of human (DU145, 22Rv1) and murine (Myc-CaP) PCa cells revealed that IGF-1 suppresses cytokine signalling, antigen processing and presentation, and additional immune regulatory pathways. We further examined the expression of components involved in cancer cell recognition and immune evasion: the antigen processing machinery and PD-L1 checkpoint. IGF-1 downregulated key elements such as transporters associated with antigen processing (TAPs), endoplasmic reticulum aminopeptidase-1 (ERAP-1), and Class I β2-microglobulin, without significantly altering Class I allele expression. These changes were associated with reduced surface presentation of Class I complexes on Myc-CaP cells, suggesting disrupted peptide transport, processing, and/or presentation. In contrast, IGF-1 upregulated the immune checkpoint CD274 (PD-L1) via IGF receptor/AKT/ERK-dependent signalling. Analysis of TCGA Firehose Legacy PCa data showed higher CD274 expression in tumors with elevated IGF1 and IGFBP5. Multiplex immunofluorescence in primary PCa confirmed increased PD-L1 in patients with high serum IGF-1, supporting its role in immune evasion. Overall, these findings reveal a novel IGF-1-driven immunosuppressive mechanism that may underlie PCa’s resistance to immunotherapy.</p>

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IGF-1 regulates cancer cell immune evasion in prostate cancer

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年11月3日

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  • Ashwin M. Nandakumar,
  • Alessandro Barberis,
  • Jinseon Kim,
  • Cameron R. Lang,
  • Jack V. Mills,
  • Guillaume Rieunier,
  • Dimitrios Doultsinos,
  • Avigail Taylor,
  • Ashwin Jainarayanan,
  • Su M. Phyu,
  • Leticia Campo,
  • Alistair Easton,
  • Eileen E. Parkes,
  • Timothy James,
  • Freddie C. Hamdy,
  • Clare Verrill,
  • Ian G. Mills,
  • Valentine M. Macaulay

摘要

Insulin-like growth factor-1 (IGF-1) is associated with prostate cancer (PCa) development and lethality and exhibits immunosuppressive properties in other models. We investigated IGF-1’s tumor-intrinsic immune effects in PCa to understand mechanisms underlying its poor immunotherapy response. Transcriptional profiling of human (DU145, 22Rv1) and murine (Myc-CaP) PCa cells revealed that IGF-1 suppresses cytokine signalling, antigen processing and presentation, and additional immune regulatory pathways. We further examined the expression of components involved in cancer cell recognition and immune evasion: the antigen processing machinery and PD-L1 checkpoint. IGF-1 downregulated key elements such as transporters associated with antigen processing (TAPs), endoplasmic reticulum aminopeptidase-1 (ERAP-1), and Class I β2-microglobulin, without significantly altering Class I allele expression. These changes were associated with reduced surface presentation of Class I complexes on Myc-CaP cells, suggesting disrupted peptide transport, processing, and/or presentation. In contrast, IGF-1 upregulated the immune checkpoint CD274 (PD-L1) via IGF receptor/AKT/ERK-dependent signalling. Analysis of TCGA Firehose Legacy PCa data showed higher CD274 expression in tumors with elevated IGF1 and IGFBP5. Multiplex immunofluorescence in primary PCa confirmed increased PD-L1 in patients with high serum IGF-1, supporting its role in immune evasion. Overall, these findings reveal a novel IGF-1-driven immunosuppressive mechanism that may underlie PCa’s resistance to immunotherapy.