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An Endocytic Checkpoint Controls Macrophage PD-1 Function and Immunotherapy Fate.

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    Researchers identified GIV (CCDC88A) in macrophages as key to PD1 blockade response. GIV loss promotes hyperprogressive disease (HPD) by disrupting PD1 receptor removal, highlighting a new target for cancer immunotherapy.

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    Area of Science:

    • Immunology
    • Cancer Biology
    • Molecular Medicine

    Background:

    • Responses to programmed cell death protein 1 (PD1) blockade therapy vary widely, from durable tumor control to hyperprogressive disease (HPD).
    • The innate immune mechanisms underlying these divergent responses to PD1 blockade are not well understood.
    • Macrophages play critical roles in antitumor immunity and response to immunotherapy.

    Purpose of the Study:

    • To identify macrophage-intrinsic factors that determine outcomes of PD1 blockade therapy, specifically distinguishing durable responses from HPD.
    • To elucidate the molecular mechanisms by which these factors regulate PD1 receptor function and trafficking in macrophages.

    Main Methods:

    • Integration of a large-scale macrophage systems atlas (>12,500 transcriptomes) with single-cell RNA sequencing data from over 1,000 patients treated with anti-PD1 therapy.
    • Functional studies in murine models, human macrophages, and patient-derived organoids involving genetic deletion or pharmacologic inhibition of CCDC88A (GIV).
    • Analysis of PD1 receptor surface retention, phagocytosis assays, and tumor growth kinetics.

    Main Results:

    • CCDC88A (GIV) was identified as a macrophage-intrinsic determinant of durable response versus HPD.
    • Loss of GIV leads to increased PD1 surface retention, suppressed phagocytosis, and accelerated tumor growth.
    • Myeloid-specific GIV deletion reprogrammed macrophages towards HPD-like states, converting PD1 blockade from tumor-restraining to tumor-accelerating.
    • Mechanistically, GIV interacts with a TIR-like [TILL] motif in the PD1 cytoplasmic tail to promote dynamin-dependent endocytosis, linking signaling to receptor trafficking.

    Conclusions:

    • PD1 receptor routing, mediated by GIV in macrophages, is a critical checkpoint governing antitumor immunity, independent of ligand binding.
    • Disruption of the GIV-PD1 endocytic axis represents an actionable vulnerability that can undermine PD1 blockade efficacy and promote accelerated tumor growth.
    • Targeting PD1 receptor trafficking in macrophages offers a novel therapeutic strategy to improve outcomes in cancer immunotherapy.