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Collagen modification remodels the sarcoma tumor microenvironment and promotes resistance to immune checkpoint

Hehai Pan, Ying Liu, Ashley M Fuller

    Biorxiv : the Preprint Server for Biology
    |July 15, 2024
    PubMed

    Insights

    Procollagen-lysine,2-oxoglutarate 5-dioxygenase 2 (Plod2) promotes immune evasion in soft tissue sarcomas. Inhibiting Plod2 with minoxidil reduces tumor growth and enhances anti-PD-1 immunotherapy efficacy in undifferentiated pleomorphic sarcoma.

    Area of Science:

    • Oncology
    • Immunology
    • Biochemistry

    Background:

    • Immune checkpoint inhibitor (ICI) response varies significantly in solid tumors, including soft tissue sarcomas (STS).
    • The molecular drivers of this heterogeneity, particularly immune evasion mechanisms in STS, are not fully understood.
    • Procollagen-lysine,2-oxoglutarate 5-dioxygenase 2 (Plod2) is over-expressed in many tumors and linked to metastasis.

    Purpose of the Study:

    • To investigate the role of Plod2 in immune evasion within undifferentiated pleomorphic sarcoma (UPS), an aggressive STS subtype.
    • To determine if Plod2 inhibition can enhance the efficacy of anti-PD-1 immunotherapy.
    • To explore Plod2 as a potential therapeutic target for augmenting cancer immunotherapy.

    Main Methods:

    • Utilized an immune-competent syngeneic transplant model of UPS.
    • Employed genetic and pharmacologic inhibition of Plod2 using minoxidil, a pan-Plod transcriptional inhibitor.
    • Assessed tumor growth and response to anti-PD-1 therapy following Plod2 modulation.

    Main Results:

    • Plod2 overexpression was found to promote immune evasion in UPS.
    • Inhibition of Plod2, via genetic or pharmacologic means (minoxidil), reduced UPS tumor growth.
    • Plod2 inhibition significantly enhanced the efficacy of anti-PD-1 therapy in this model.
    • Plod2's enzymatic target, collagen type VI (ColVI), was implicated in CD8+ T cell dysfunction.

    Conclusions:

    • Plod2 is identified as a key mediator of immune evasion in undifferentiated pleomorphic sarcoma.
    • Targeting Plod2 represents a promising strategy to overcome resistance to immunotherapy.
    • Modulating Plod2 activity could improve responses to anti-PD-1 therapy in UPS and potentially other cancers.

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