Biology subjects

Bourdely, P.

Publications and source records attributed to Bourdely, P..

5 recordsLinked to original sources

bioRxiv2025

Intra-tumoral delivery of FLT3L with CXCR3/CCR5 ligands promotes XCR1+ DC1 infiltration and activates anti-tumor immunity

Tumor infiltration by XCR1 conventional dendritic cells (cDC1) correlates strongly with favorable prognosis and improved responses to immunotherapy. Yet, tumor-driven immunosuppressive programs restrict efficient cDC1 recruitment, highlighting the need for strategies increasing cDC1 access to the tumor microenvironment. Here, we establish a proof-of-concept cell-based immunotherapy that enhances the infiltration of circulating cDC1 progenitors and supports their local expansion. Intratumoral engraftment of autologous mesenchymal stromal cells engineered to express membrane bound FLT3L promotes cDC1 recruitment when combined with poly(I:C). We identify poly(I:C)-induced CXCL9 and CCL5 as essential chemokines controlling intratumoral cDC1 infiltration. Stromal cell-mediated local delivery of FLT3L together with CXCL9 and CCL5 is sufficient to enhance cDC1 infiltration in mice or humanized mice settings. Finally, this approach activates antitumor immunity and partially overcomes resistance to immune checkpoint blockade. Collectively, our data support the therapeutic potential of expanding intratumoral cDC1s through local and sustained delivery of FLT3L, CXCL9, and CCL5.

immunology↗

bioRxiv2025

The Rab32 small GTPase is required for efficient cross-priming of CD8+ T cellsagainst cell-associated antigens by XCR1+ type 1 DCs in vivo.

Type 1 conventional dendritic cells (cDC1s) are critical for initiating adaptive immune responses through the cross-priming of CD8 T cells against antigens from tumor or virus-infected cells. This function depends on specialized cross-presentation pathways that allow cDC1s to process phagocytosed cell debris and present peptide-MHC I complexes. In this study, we identify the small GTPase Rab32 as being highly and selectively over-expressed in cDC1s as compared to cDC2s. While cDC1s from Rab32-deficient mice develop normally and can respond to maturation signals, their capacity to activate CD8 T cells in vivo is impaired. Notably, Rab32- deficient cDC1s retain the ability to stimulate TCR transgenic CD8 T cells ex vivo using both cell-associated antigens and MHC I-binding peptides of varying affinity. However, in vivo, Rab32 is essential for effective CD8 T cell responses to cell-associated antigens, independent of Rab32 expression in T cells themselves. Importantly, Rab32-mediated cross-priming is required for the efficient expansion of tumor-specific CD8 T cells into solid tumors. These findings underscore a critical role for Rab32 in cDC1-mediated cross-priming, highlighting the contribution of non-antigen processing vesicular pathways in shaping CD8 T cell responses to cellular antigens.

immunology↗

bioRxiv2024

Fc immunoreceptors promote autophagy to regulate monocyte functions

Receptors for the Fc fragment of immunoglobulin G (FcyRs) are critical in the defense against pathogens and in monoclonal antibody-based therapies. When activated by immune complexes or opsonized particles, FcyRs are endocytosed. Components of the endocytosis machinery are used during autophagy, a process which is triggered by starvation or by activation of specific receptors. In this work, we demonstrate that activation of FcyRs initiates autophagy, characterized by formation of p62 protein puncta and activation of ULK1, a major component of the autophagy initiation complex. Autophagy induction downstream of FcyRs activation involves the protein phosphatase Pp2a and its enzymatic activity, as demonstrated by in situ protein labeling. In animal models in which autophagy was inactivated or enhanced in myeloid cells, autophagy negatively regulates pro-inflammatory cytokine production downstream of FcyRs receptors, while being required for FcyRs -mediated antibody-induced cell phagocytosis and myeloid cell survival. Our results suggest that, for antibody-based therapeutic strategies that target the activation of FcyRs, an additional level of control can be obtained by manipulation of autophagy.

cell biology↗

bioRxiv2024

DCs targeted therapy expands CD8 T cell responses to bona-fide neoantigens in lung tumors

Cross-presentation by type 1 cDCs (cDC1) is critical to induce and sustain antitumoral CD8 T cell responses to model antigens, in various tumor settings. However, the impact of cross-presenting cDC1 and the potential of DC-based therapies in tumors carrying varied levels of bona-fide neoantigens (neoAgs) remains unclear. Here we generated a non-small cell lung cancer model with distinct ranges of TMB and MHC-I neoepitopes to test immunogenicity and response to Flt3L+CD40 (DC-therapy). We found that cDC1 are required to broaden the pattern of CD8 responses to basal and acquired neoAgs and DC-therapy strongly inhibits the growth of TMBhigh tumors. In contrast, TMBlow tumors induce weaker responses that are not sufficient to block progression. scRNA transcriptional analysis, immune profiling and functional assays show that DC-therapy triggers the accumulation of lung cDC1 with increased immunostimulatory properties and CD8 T cells with enhanced cytotoxic functions and reduced exhaustion, most prominently in neoAgshigh tumors. We conclude that boosting cDC1 activity is critical to broaden the diversity of anti-tumoral CD8 T cell responses and to leverage neoAgs content for therapeutic advantage.

immunology↗

bioRxiv2019

Engineered niches support the development of human dendritic cells in humanized mice

Classical dendritic cells (cDCs) are rare sentinel cells specialized in the regulation of adaptive immunity. Modeling cDC development is both crucial to study cDCs and harness their potential in immunotherapy. Here we addressed whether cDCs could differentiate in response to trophic cues delivered by mesenchymal components of the hematopoietic niche where they physiologically develop and maintain. We found that expression of the membrane bound form of human FLT3L and SCF together with CXCL12 in a bone marrow mesenchymal stromal cell line is sufficient to induce the contact-dependent specification of both type 1 and type 2 cDCs from CD34+ hematopoietic stem and progenitor cells (HSPCs). Engraftment of these engineered mesenchymal stromal cells (eMSCs) together with CD34+ HSPCs creates an in vivo synthetic niche in the dermis of immunodeficient mice. Cell-to-cell contact between HSPCs and stromal cells within these organoids drive the local specification of cDCs and CD123+AXL+CD327+ pre/AS-DCs. cDCs generated in vivo display higher levels of resemblance with human blood cDCs unattained by in vitro generated subsets. Altogether, eMSCs provide a novel and unique platform recapitulating the full spectrum of cDC subsets enabling their functional characterization in vivo.

immunology↗