IGF-1 regulates cancer cell immune evasion in prostate cancer

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. Transc...

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Bibliographic Details
Published in:Scientific reports Vol. 15; no. 1; pp. 38422 - 10
Main Authors: Nandakumar, Ashwin M., Barberis, Alessandro, Kim, Jinseon, Lang, Cameron R., Mills, Jack V., Rieunier, Guillaume, Doultsinos, Dimitrios, Taylor, Avigail, Jainarayanan, Ashwin, Phyu, Su M., Campo, Leticia, Easton, Alistair, Parkes, Eileen E., James, Timothy, Hamdy, Freddie C., Verrill, Clare, Mills, Ian G., Macaulay, Valentine M.
Format: Journal Article
Language:English
Published: London Nature Publishing Group UK 03.11.2025
Nature Publishing Group
Nature Portfolio
Subjects:
631/67
631/67/580
AKT protein
Aminopeptidase
Androgens
Animals
Antigen Presentation
Antigen processing
Autophagy
B7-H1 Antigen - genetics
B7-H1 Antigen - metabolism
Cell cycle
Cell Line, Tumor
Cell recognition
Cytokines
Down-regulation
Endoplasmic reticulum
Gene Expression Regulation, Neoplastic
Genes
Humanities and Social Sciences
Humans
Immune checkpoint
Immune Evasion
Immune response
Immunofluorescence
Immunotherapy
Insulin-like growth factor I
Insulin-Like Growth Factor I - genetics
Insulin-Like Growth Factor I - immunology
Insulin-Like Growth Factor I - metabolism
Insulin-like growth factor-binding protein 5
Insulin-like growth factors
Lethality
Lupus
Male
Metastasis
Mice
multidisciplinary
Myc protein
PD-L1 protein
Peptides
Prostate cancer
Prostatic Neoplasms - genetics
Prostatic Neoplasms - immunology
Prostatic Neoplasms - metabolism
Prostatic Neoplasms - pathology
Proteins
Science
Science (multidisciplinary)
Signal processing
Signal Transduction
Tumor Escape
β2 Microglobulin
ISSN:2045-2322, 2045-2322
Online Access:Get full text
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Summary: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.
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ISSN:2045-2322
2045-2322
DOI:10.1038/s41598-025-22288-5