Biology subjects

Straetemans, T.

Publications and source records attributed to Straetemans, T..

3 recordsLinked to original sources

bioRxiv2025

Functional γδT-omics pipeline reveals compartmentalization of Vδ1⁺ T cell migration, tumor-reactivity, and clonality in human colorectal cancer

{gamma}{delta}T cells play a pivotal role in cancer immune surveillance, yet the current knowledge of their function across the compartments in solid tumors is meager. To address this gap, we developed a comprehensive {gamma}{delta}T-omics platform that integrates functional screening, biomimetic migration assays, {gamma}{delta}TCR repertoire analysis, and transcriptomic profiling. Using matched samples from 31 patients with microsatellite-stable colorectal cancer (CRC), we analyzed {gamma}{delta}T cells from peripheral blood (PBLs{gamma}{delta}), adjacent colon (LPLs{gamma}{delta}), primary tumors (pTILs{gamma}{delta}), and liver metastases (mTILs{gamma}{delta}). This approach uncovered striking compartmentalization of {gamma}{delta}T cell phenotypes, clonality, and function. Tumor-reactive, clonally expanded V{delta}1 {gamma}{delta}T cells were enriched in primary tumors and shared transcriptional and functional features with lamina propria lymphocytes (LPLs). In contrast, V{delta}1 {gamma}{delta}T cells from liver metastases lacked tumor reactivity, exhibited distinct {gamma}{delta}TCR repertoires, and expressed transcriptional signatures associated with TGF-{beta}-mediated suppression and cellular quiescence, suggesting they are shaped by tissue-specific environmental cues. CXCL16 secretion by tumor cells initiated V{delta}1 LPLs{gamma}{delta} migration, which was further amplified by {gamma}{delta}TCR-mediated CCL5 induction from pTILs{gamma}{delta}, leading to CCR5 downregulation and subsequent entrapment of pTILs{gamma}{delta} within the tumor microenvironment. Accordingly, our clinical data from an independent second cohort of 69 patients showed that infiltration by pTILs{gamma}{delta}, but not mTILs{gamma}{delta}, is associated with a protective effect against CRC progression. In summary, our study offers a compartment-resolved perspective on {gamma}{delta}T cell behavior in CRC, revealing key trafficking and functional mechanisms, and enabling the identification of novel tumor-reactive {gamma}{delta}TCRs and migratory cues to inform immunotherapeutic strategies for both primary and metastatic CRC. Graphical abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=179 SRC="FIGDIR/small/671055v1_ufig1.gif" ALT="Figure 1"> View larger version (54K): org.highwire.dtl.DTLVardef@ff3bborg.highwire.dtl.DTLVardef@14a7e1forg.highwire.dtl.DTLVardef@19e4de4org.highwire.dtl.DTLVardef@bc600_HPS_FORMAT_FIGEXP M_FIG C_FIG

immunology↗

bioRxiv2024

Sensitivity to Vγ9Vδ2TCR T cells is imprinted after single mutations during early oncogenesis

V{gamma}9V{delta}2T cells have the unique ability to recognize a broad range of malignant transformed cells. The tumor targeting event involving BTN2A1 and BTN3A1 dimers on the tumor cell surface is critical, leading to full activation of the TCR. Although the molecular mechanisms governing TCR engagement and T cell activation are well-characterized, the role of V{gamma}9V{delta}2 T cells in cancer immune surveillance remains to be fully elucidated, particularly the mechanisms that enable these cells to discriminate between healthy and malignant cells at an early stage of malignant transformation. We employed two independent, genetically engineered step-wise mutagenesis models of human colorectal and breast cancer that mimic the transformation steps leading to tumor formation. We demonstrate that various single oncogenic mutations introduced into healthy organoids or cells, are sufficient to upregulate surface expressed BTN2A1 and enable V{gamma}9V{delta}2 TCR binding to tumor cells. However, full activation of T cells through a V{gamma}9V{delta}2TCR required additional subsequent phosphorylation of juxtamembrane (JTM) amino acids of BTN3A1, leading to the activating heterodimerization of BTN2A1 and 3A1. Using a protein interactome mapping pipeline, we identified PHLDB2, SYNJ2 and CARMIL1 as key players in controlling these delicate dual surface dynamics of BTN2A1 and 3A1 during early transformation. This mode of action allowed V{gamma}9V{delta}2TCR T cells to control tumors in vitro and in vivo, emphasizing the crucial role of these molecules from early mutagenesis, to advanced cancer stages, and highlighting the therapeutic potential of a V{gamma}9V{delta}2TCR.

cancer biology↗

bioRxiv2021

Enhancing cancer targeting of γ9δ2TCR through modified NKG2D co-stimulation

Despite the ability of {gamma}{delta}T cells to mediate tumor killing independently of MHC recognition, all the clinical trials that have been carried out using these cells showed low response rate in patients, in part due to its poor proliferation ability. Recently, a new generation of CAR-T cells called {beta}T cells engineered to express a defined {gamma}{delta}TCR (TEG) has been developed. TEGs are {beta}T cells engineered to express a defined {gamma}{delta}TCR. These cells are able to mediate effective antitumor reactivity without showing any reactivity towards healthy tissue, and combine the best qualities of both {beta}T and {gamma}{delta}T cells. In fact, the high affinity {gamma}9{delta}2TCR clone 5 has recently been selected within the TEG format as a clinical candidate (TEG001). Here we present a strategy to improve the antitumor activity of TEG001 by co-expressing an activating chimeric co-receptor together with {gamma}{delta}TCR-Cl5.Therefore, we developed three different co-receptors by fusing the extracellular domain of the activating cell surface receptor NKG2D, that is able to bind stress induced ligands typically expressed on tumor cells, to the cytoplasmic signaling domains of the T cell costimulatory proteins ICOS, CD28 and 4-1BB. We determined that introduction of the chimeric co-receptors NKG2D-CD28wt and NKG2D-4-1BBCD28TM improved the activity of TEG001 against tumors that were recognized by {gamma}{delta}TCR-Cl5 and expressed NKG2D ligands, but did not affect tumors that either were not recognized by {gamma}{delta}TCR-Cl5 or did not express NKG2D ligands. This chimeric co-receptors approach open a wide range of opportunities that lead to a next generation of TEGs.

immunology↗