Biology subjects

McLaren, E.

Publications and source records attributed to McLaren, E..

2 recordsLinked to original sources

bioRxiv2026

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

Responses to PD1 blockade span durable tumor control to hyperprogressive disease (HPD), yet innate immune mechanisms governing these extremes remain undefined. Here we integrate a macrophage systems atlas (>12,500 transcriptomes) with single-cell profiles from >1,000 anti-PD1 treated patients, to identify CCDC88A (GIV) as a macrophage-intrinsic determinant of durable response versus HPD. GIV loss increases PD1 surface retention, suppresses phagocytosis, and accelerates tumor growth across murine models, human macrophages, and patient-derived organoids. Myeloid-specific GIV deletion converts PD1 blockade from tumor-restraining to tumor-accelerating by reprogramming macrophages toward HPD-like states. Mechanistically, GIV engages a conserved TIR-like [TILL] motif within the PD1 cytoplasmic tail to drive dynamin-dependent endocytosis, coupling innate immune signaling logic to checkpoint receptor trafficking. Pharmacologic disruption of this axis phenocopies GIV loss, revealing an endocytic vulnerability that undermines checkpoint efficacy and triggers accelerated growth at relapse. These findings define PD1 routing, rather than ligand-binding, as a macrophage-encoded checkpoint governing antitumor immunity. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=200 SRC="FIGDIR/small/718292v1_ufig1.gif" ALT="Figure 1"> View larger version (65K): org.highwire.dtl.DTLVardef@a8f83aorg.highwire.dtl.DTLVardef@140dc7dorg.highwire.dtl.DTLVardef@14bc366org.highwire.dtl.DTLVardef@1096b8a_HPS_FORMAT_FIGEXP M_FIG GRAPHIC ABSTRACT C_FIG In briefMullick et al. show that PD1 trafficking in tumor associated macrophages (TAMs), controlled by the endocytic adaptor GIV/Girdin, determines the durability of immunotherapy. Disrupting this pathway traps PD1 at the surface, converts checkpoint blockade into hyperprogressive disease, and abolishes therapeutic benefit, revealing PD1 routing as a macrophage-encoded checkpoint of immunotherapy outcome. HighlightsO_LIGIV defines macrophage states that stratify durable response vs hyperprogressive disease C_LIO_LIGIV limits surface checkpoint accumulation by facilitating PD1 endocytosis C_LIO_LILoss of GIV traps PD1 at the membrane and drives hyperprogressive disease C_LIO_LIEndocytic blockade phenocopies GIV loss and abolishes checkpoint efficacy C_LIO_LIPsychotropic drugs disrupt PD1 trafficking and accelerate tumor growth C_LI

cancer biology↗

bioRxiv2026

A Druggable G Protein Checkpoint in Cholesterol Efflux

Immunometabolic diseases such as obesity, fatty liver, and atherosclerosis arise when lipid-associated macrophages (LAMs) fail to resolve lipid overload via reverse cholesterol transport (RCT), the bodys sole pathway for lipid disposal. How RCT is restrained in disease remains unknown. Integrating systems modeling with human plaque transcriptomes, we identify LAM subpopulations associated with plaque progression and uncover CCDC88A (GIV) as a macrophage-intrinsic checkpoint on RCT. Myeloid-specific GIV deletion in mice reduces aortic plaque burden, mobilizes hepatic and adipose lipid stores and promotes fecal sterol disposal. Mechanistically, GIV sequesters the cholesterol transporter ABCA1 within endomembranes and activates Gi[bullet]{beta}{gamma} signaling to suppress cAMP/PKA-CREB-dependent efflux programs. Pharmacogenomic disruption of this checkpoint reactivates efflux programs. In human plaque-in-a-dish models targeting this pathway restored efflux where statins and {beta}-blockers failed, translating to an estimated [~]98% reduction in plaque-progression risk in outcome modeling. Thus, RCT-restoration represents a macrophage-intrinsic therapeutic paradigm for immunometabolic disease. GRAPHIC ABSTRACT O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=199 SRC="FIGDIR/small/705962v2_ufig1.gif" ALT="Figure 1"> View larger version (64K): org.highwire.dtl.DTLVardef@50dd10org.highwire.dtl.DTLVardef@e16d9borg.highwire.dtl.DTLVardef@1e2eaf3org.highwire.dtl.DTLVardef@af29b9_HPS_FORMAT_FIGEXP M_FIG C_FIG eTOC blurbLipid-associated macrophages drive immunometabolic disease. Katkar et al. show that disabling a GIV-dependent G-protein brake restores cholesterol efflux, reverses plaque lipid accumulation, and establishes reverse cholesterol transport as a druggable therapeutic axis. HighlightsO_LIStatins slow but rarely reverse plaque burden, leaving residual risk driven by LAM dysfunction C_LIO_LIGIV (CCDC88A) non-canonically modulates Gi to suppress macrophage cholesterol efflux C_LIO_LIGIV loss or inhibition restores ABCA1 activity via transcriptional and post-translational control C_LIO_LIBlocking GIV[bullet]Gi checkpoint defats LAMs, regresses plaques, and relieves systemic lipid overload C_LIO_LISIdentifies a druggable node that redefines RCT restoration as a therapeutic paradigm in immunometabolic disease C_LI

immunology↗