Biology subjects

Delisle, J.-S.

Publications and source records attributed to Delisle, J.-S..

3 recordsLinked to original sources

bioRxiv2025

Cryptic leukemia antigens share homology with microbial epitopes and stimulate T-cell responses in healthy donors

Leukemia cells express cryptic tumor-specific antigens (TSAs) derived from aberrantly transcribed non-exomic genome sequences. These antigens are generally absent from healthy tissues yet shared across patients, making them attractive immunotherapy targets by minimizing on-target/off-tumor toxicity while offering broad applicability. However, their immunogenic potential and the nature of the T-cell repertoire they stimulate remain unknown. Cryptic antigen-specific CD8+ T cells could be expanded from healthy donor T-cell repertoires for six out of nine candidate acute leukemia cryptic TSA. T-cell receptor (TCR) and epitope sequence analysis revealed oligoclonal or near-monoclonal responses, involving shared and donor-restricted clonotypes recognizing cryptic TSAs which shared sequence homology with microbial epitopes. Orthotopic TCR replacement with cryptic TSA-specific TCR chains using a one-step CRISPR-Cas9 approach further validated the antigenic specificity and therapeutic potential of two TCRs respectively targeting cryptic TSAs from acute myeloid and lymphoid leukemia. To our knowledge, this is the first report describing functional TCRs directed against cryptic leukemia TSAs and highlights their potential as a new class of antigens for T-cell-based immunotherapies. Key pointsO_LIA high proportion of cryptic leukemia TSAs shares homology with microbial epitopes and can stimulate expansion of low-frequency T cell repertoire in healthy individuals. C_LIO_LIEx vivo expansion of cryptic TSA-specific T cells enables TCR identification that can be used to devise new T cell immunotherapies. C_LI Visual Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=122 SRC="FIGDIR/small/691479v1_ufig1.gif" ALT="Figure 1"> View larger version (30K): org.highwire.dtl.DTLVardef@1bd720dorg.highwire.dtl.DTLVardef@8ac6d6org.highwire.dtl.DTLVardef@104289aorg.highwire.dtl.DTLVardef@5a65e_HPS_FORMAT_FIGEXP M_FIG C_FIG ConclusionCryptic leukemia antigens elicit antigenic and specific T-cell responses and represents novel targets for TCR or BiTE immunotherapy.

immunology↗

bioRxiv2023

Combined inhibition of homologous PTPN1 and PTPN2 is synergistic in enhancing CD8 T cell effector functions.

Increased understanding of the modulatory pathways controlling CD8 T cell responses has led to the formulation of successful checkpoint inhibitor-based immunotherapies against cancer. However, their effectiveness is limited to a few tumor types, motivating the search for novel combinatorial strategies. PTPN1 and PTPN2 are two homologous protein tyrosine phosphatases recently proposed as potent intracellular checkpoints. Furthermore, their catalytic domain is a propitious target for small-molecule pharmacological intervention. Herein we investigated the potential effects of conditional genetic deletion of either or both phosphatases in mouse CD8 T cells, one of the main effectors in cancer immunotherapy. Our results demonstrated that hemizygous deletion of PTPN1 in a PTPN2 deficient background heightens the enhanced effector phenotype already observed in PTPN2 defective CD8 T cells. This functional gain is mediated by an autocrine IL-10 positive feedback loop. Pharmacological inhibition with a PTPN1/2 small-molecule inhibitor yielded similar results, highlighting the importance of simultaneously inhibiting both phosphatases. Our study uncovers a novel mechanism by which the downregulation of PTPN1 and PTPN2 act as a powerful tool for potentiating CD8 cytotoxic responses.

immunology↗

bioRxiv2022

CBFA2T3-GLIS2-dependent pediatric acute megakaryoblastic leukemia is driven by GLIS2 and sensitive to Navitoclax

Pediatric acute megakaryoblastic leukemia (AMKL) is an aggressive, uncurable blood cancer associated with poor therapeutic response and high mortality. We developed CBFA2T3-GLIS2-driven mouse models of AMKL that recapitulate the phenotypic and transcriptional signatures of the human disease. We show that an activating Ras mutation, which occurs in human AMKL, increased the penetrance and decreased the latency of CBF2AT3-GLIS2-driven AMKL. CBFA2T3-GLIS2 and GLIS2 modulate similar transcriptional networks. We uncover the dominant oncogenic properties of GLIS2, which trigger AMKL in cooperation with oncogenic Ras. We find that both CBFA2T3-GLIS2 and GLIS2 alter the expression of numerous BH3-only proteins, causing AMKL cell sensitivity to the BCL-2 inhibitor navitoclax both in vitro and in vivo, suggesting a novel therapeutic option for pediatric patients suffering from CBFA2T3-GLIS2-driven AMKL. Key pointsGLIS2 cooperates with activated Nras to promote the development of acute megakaryoblastic leukemia. CBFA2T3-GLIS2 and GLIS2 alter the expression of BCL2 family members rendering AMKL cells sensitive to navitoclax.

cancer biology↗