Biology subjects

Harle, D. W.

Publications and source records attributed to Harle, D. W..

3 recordsLinked to original sources

bioRxiv2025

Conserved Landscape of Chemokine Receptor Co-expression Defines the Functional States of CD8+ T Cells in Melanoma

Cancer immunotherapies, from checkpoint blockade to adoptive cell therapies like tumor-infiltrating lymphocytes (TILs), have revolutionized cancer treatment but are limited by variable efficacy and significant toxicities. A central challenge is identifying ideal T-cell populations that effectively eliminate tumors without causing off-target damage, a distinction not captured by existing biomarkers. We show that co-expression patterns of chemokine receptors (CRs) CXCR3, CCR5, and CXCR6 on CD8+ T cells provide a functional "code" defining subsets with divergent roles in on-target immunity versus off-target inflammation. In mouse and human melanoma, a triple-positive (CXCR3+CCR5+CXCR6+) T-cell subset is essential for tumor control, and its genetic signature correlates with positive clinical response, while a distinct CCR5+CXCR6+ subset drives liver immune-related adverse events (IRAEs). Crucially, this CR code reveals that immunotherapy actively reshapes T-cell trafficking patterns, uncovering profound heterogeneity within conventional populations and distinguishing potent anti-tumor progenitors from cells predisposed to exhaustion or off-target migration. This work establishes CR co-expression as a practical tool, providing a surface marker-based strategy to identify and enrich optimized T cells for adoptive therapies, thereby offering a framework to uncouple efficacy from toxicity. One Sentence SummaryCo-expression of CCR5, CXCR6, and CXCR3 provides a functional code that separates T-cell-mediated anti-tumor efficacy from off-target toxicity, enabling the selection of superior cells for safer and more effective cancer immunotherapies. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=120 SRC="FIGDIR/small/693486v2_ufig1.gif" ALT="Figure 1"> View larger version (29K): org.highwire.dtl.DTLVardef@19b0f44org.highwire.dtl.DTLVardef@1076129org.highwire.dtl.DTLVardef@17c0be6org.highwire.dtl.DTLVardef@f14893_HPS_FORMAT_FIGEXP M_FIG C_FIG HighlightsO_LI{middle dot} CXCR6, CXCR3 and CCR5 co-expression signature stratifies patient survival in human melanoma C_LIO_LI{middle dot} CD8+ T cells co-expressing CXCR6, CXCR3 and CCR5 are critical effectors with high proliferative, cytotoxic, and activation profile in human and mice melanoma C_LIO_LI{middle dot} CD8+ T cells co-expressing CXCR6, CXCR3 and CCR5 drive anti-tumoral responses during checkpoint blockade in both human and mice C_LI

immunology↗

bioRxiv2025

Spatiotemporal Single-Cell Analysis Reveals T Cell Clonal Dynamics and Phenotypic Plasticity in Human Graft-versus-Host Disease

Allogeneic hematopoietic cell transplantation (alloHCT) is curative for various hematologic diseases but often leads to acute graft-versus-host disease (GVHD), a potentially life-threatening complication. We leverage GVHD as a uniquely tractable disease model to dissect complex T-cell-mediated pathology in 27 alloHCT recipients. We integrate pre-transplant identification of alloreactive T-cells with longitudinal tracking across blood and gut, using mixed lymphocyte reaction-based clonal "fingerprinting", TCR clonotyping, single-cell RNA/TCR sequencing, and spatial transcriptomics. Using DecompTCR, a novel computational tool for longitudinal TCR analysis, we uncover clonal expansion programs linked to GVHD severity and TCR features. Multi-omics profiling of gut biopsies reveals enrichment and clonal expansion of CD8 effector and ZNF683(Hobit) resident memory T-cells, cytolytic remodeling of regulatory and unconventional T-cells, and localization of CD8 effector T-cells near intestinal stem cells in crypt loss regions. This framework defines dynamic immune circuit rewiring and phenotypic plasticity with implications for biomarkers and therapies. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=198 SRC="FIGDIR/small/655962v1_ufig1.gif" ALT="Figure 1"> View larger version (45K): org.highwire.dtl.DTLVardef@178b77dorg.highwire.dtl.DTLVardef@569226org.highwire.dtl.DTLVardef@1951281org.highwire.dtl.DTLVardef@1f1e046_HPS_FORMAT_FIGEXP M_FIG C_FIG HighlightsO_LIPersistent expansion of diverse alloreactive T cell clones is a hallmark of severe GVHD C_LIO_LIDecompTCR reveals dynamic clonal expansion programs linked to GVHD severity and clinical outcome C_LIO_LICD8+ T cell clones exhibit phenotypic plasticity in vivo across intestinal tissue compartments in GVHD C_LIO_LIHigh-resolution spatial profiling shows CD8+ effector T cells localize near intestinal stem cell niches and drive epithelial injury in GVHD C_LI

systems biology↗

bioRxiv2024

A CXCR4 partial agonist improves immunotherapy by targeting polymorphonuclear myeloid-derived suppressor cells and cancer-driven granulopoiesis

Polymorphonuclear myeloid-derived suppressor cells (PMN-MDSCs) are pathologically activated neutrophils that potently impair immunotherapy responses. The chemokine receptor CXCR4, a central regulator of hematopoiesis, represents an attractive PMN-MDSC target1. Here, we fused a secreted CXCR4 partial agonist TFF2 to mouse serum albumin (MSA) and demonstrated that TFF2-MSA peptide synergized with anti-PD-1 to induce tumor regression or eradication, inhibited distant metastases, and prolonged survival in multiple gastric cancer (GC) models. Using histidine decarboxylase (Hdc)-GFP transgenic mice to track PMN-MDSC in vivo, we found TFF2-MSA selectively reduced the immunosuppressive Hdc-GFP+ CXCR4hi tumor PMN-MDSCs while preserving proinflammatory neutrophils, thereby boosting CD8+ T cell-mediated anti-tumor response together with anti-PD-1. Furthermore, TFF2-MSA systemically reduced PMN-MDSCs and bone marrow granulopoiesis. In contrast, CXCR4 antagonism plus anti-PD-1 failed to provide a similar therapeutic benefit. In GC patients, expanded PMN-MDSCs containing a prominent CXCR4+LOX-1+ subset are inversely correlated with the TFF2 level and CD8+ T cells in circulation. Collectively, our studies introduce a strategy of using CXCR4 partial agonism to restore anti-PD-1 sensitivity in GC by targeting PMN-MDSCs and granulopoiesis.

cancer biology↗