Biology subjects

Michaud, H.-A.

Publications and source records attributed to Michaud, H.-A..

4 recordsLinked to original sources

bioRxiv2024

Deciphering the tumor-infiltrating CD73+ regulatory gammadelta T cell ecosystem associated with poor survival of patients with ovarian cancer

The ability of tumor cells to overcome immune surveillance is an essential step in tumor development and progression. Among the immune cells playing a role in tumor control, {gamma}{delta} T cells contribute to the immune response against many tumor types through their direct cytotoxic activity against cancer cells and their capacity to regulate the functions of other immune cells. However, their presence in the tumor microenvironment is also associated with poor prognosis, suggesting that {gamma}{delta} T cells may also have pro-tumor activities. We previously described a regulatory {gamma}{delta} T-cell subset that expresses CD73 and produces IL-10, IL-8 and adenosine. Here, we report a higher CD73+ {gamma}{delta} T cell density in the tumor microenvironment of ovarian cancer samples from patients with short-term than long-term survival. Starting from this original observation, we investigated their neighborhood and described a specific ecosystem according to their pro-tumor functions.

cancer biology↗

bioRxiv2024

FSTL3 is a biomarker of poor prognosis and is associated with immunotherapy resistance in ovarian cancer.

High-grade serous ovarian carcinoma (HGSOC), is associated with high mortality rates due to late-stage diagnosis and limited treatment options. We investigated the role of FSTL3 in ovarian cancer progression both as a prognostic biomarker and as a potential therapeutic target. We measured levels of follistatin (FST) and follistatin-like 3 (FSTL3) in 96 ovarian cancer patient ascites samples and found that FSTL3 overexpression was more predominant than FST and associated with poorer survival outcomes. Mice implanted with an HGSOC syngeneic cell line bearing common alterations in ovarian cancer (KRASG12V, P53R172H, CCNE1oe, AKT2oe) had increasing levels of FST and FSTL3 in serum during tumor growth. Further alteration of this model to generate a knockout of FST (KPCA.FSTKO) and an overexpression of human FSTL3 (KPCA.FSTKO_hFSTL3), revealed that FSTL3 expression was associated with a more fibrotic tumor microenvironment, correlating with an increased abundance of cancer-associated myofibroblasts (myCAFs), and cancer cells with a more mesenchymal phenotype. Tumors overexpressing FSTL3 had less immunocyte infiltration and a significantly reduced intratumoral T-cell abundance (CD4+, CD8+). FSTL3 overexpression completely abrogated tumor response to PPC treatment (Prexasertib combined with PD-1 and CTLA-4 blockade) compared to controls, suggesting that FSTL3 may be involved in immunotherapy resistance. In conclusion, this study suggests a role for FSTL3 as a prognostic marker and as therapeutic target in HGSOC, where it may play a role in promoting a mesenchymal tumor phenotype, maintaining an immunosuppressive tumor microenvironment, and driving immunotherapy resistance. HighlightsHigh FSTL3 levels are associated with poor outcomes in ovarian cancer. Serum levels of FSTL3 increase during tumor growth and reflect tumor burden and therapy response. Overexpression of FSTL3 in cancer cells promotes a fibrotic tumor microenvironment and immunocyte exclusion. Overexpression of FSTL3 in tumors induces resistance to Chk1 and immune checkpoint inhibitor combination therapy. Graphical abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=180 SRC="FIGDIR/small/627747v1_ufig1.gif" ALT="Figure 1000"> View larger version (45K): org.highwire.dtl.DTLVardef@16d0608org.highwire.dtl.DTLVardef@a70028org.highwire.dtl.DTLVardef@1fb4895org.highwire.dtl.DTLVardef@5a42b4_HPS_FORMAT_FIGEXP M_FIG C_FIG

cancer biology↗

bioRxiv2024

Acute dietary methionine restriction highlights sensitivity of neocortex development to metabolic variations

Methionine -an essential amino acid that has to be provided by nutrition- and its metabolite S-Adenosyl methionine (SAM) are indispensable for cell proliferation, stem cell maintenance and epigenetic regulation 1-5, three processes that are central to embryonic development 6. Previous studies using chronic dietary restriction of methyl donors prior to and during gestation indicated that methionine restriction (MR) is detrimental to the development or growth of the neocortex 7,8, however, the consequences of acute MR have not been extensively studied. Here, we designed a dietary MR regime coinciding with the neurogenic phases of neocortex development in the mouse. Our results indicate that dietary MR for 5 days leads to a severe reduction in neocortex growth and neuronal production. In comparison, growth of the liver and heart was unaffected, highlighting an organ-specific response to MR which was also observed at the cellular and molecular levels. Progenitor cohort labeling revealed a time-dependent sensitivity to MR and cell cycle analyses indicated that after 5 days of MR, progenitors are stalled in the S/G2 phases. Unexpectedly, neocortex growth reduction induced after 5 days of MR is completely rescued at birth when switching the dam back to control diet for the remaining of gestation, uncovering a mechanism of catch-up growth. Using multiplexed imaging we probed metabolic and epigenetic markers following MR and during catch-up growth and show that pyruvate metabolism is rewired in progenitors. Altogether, our data uncover a transient state of quiescence in G2/S which is metabolically distinct from G0 quiescence and associated with efficient catch-up growth. More globally, our study highlights both the extreme sensitivity of the developing neocortex to acute dietary changes and its remarkable plasticity.

developmental biology↗

bioRxiv2023

Spatial mapping of rheumatoid arthritis synovial niches reveals specific macrophage networks associated with response to therapy

Rheumatoid arthritis (RA) is a chronic inflammatory autoimmune disease affecting peripheral joints and for which approximately 40% of the patients respond insufficiently to the available synthetic or biologic disease modifying anti-rheumatic drugs (DMARDs). The infiltration of the synovial membrane by lymphocytes and monocytes profoundly alters its homeostatic functions, leading to chronic joint inflammation and bone destruction. A better understanding of how DMARDs impact the complex synovial cell social network in relationship to response/ non-response remains an unmet need to design more targeted and active therapeutic strategies. Here, we used imaging mass cytometry (IMC) to comparatively profile more than 115,000 cells in the synovial tissue of healthy, low inflammatory osteoarthritis and matched active early treatment-naive RA patients at baseline and at 6 months after starting DMARDs treatment. We notably highlighted that tissue resident macrophages (LYVE1+CD206+) in perivascular synovial niches encompassing specific subsets of vascular cells, fibroblasts and immune cells vanished in active RA but were recovered in response to DMARDs treatment. Combined ligand-receptor analysis of single-cell RNA sequencing datasets identified that IL10, C-type lectin or TAM (TYRO3, AXL and MERTK) receptors were particularly involved in the restoration of these spatial cell interactions in the context of clinical remission. In addition to providing an unprecedented synovial spatial mapping, our work uncovered novel potential cellular and molecular targets for the development of therapies for RA. One Sentence SummarySingle-cell spatial profiling of rheumatoid arthritis synovium identifies specific cell states linked to treatment response

immunology↗