Urban Community of Lyon

Owing to a long history of anthropogenic pressures, freshwater ecosystems are among the most vulnerable to biodiversity loss1. Mitigation measures, including wastewater treatment and hydromorphological restoration, have aimed to improve environmental quality and foster the recovery of freshwater biodiversity2. Here, using 1,816 time series of freshwater invertebrate communities collected across 22 European countries between 1968 and 2020, we quantified temporal trends in taxonomic and functional diversity and their responses to environmental pressures and gradients. We observed overall increases in taxon richness (0.73% per year), functional richness (2.4% per year) and abundance (1.17% per year). However, these increases primarily occurred before the 2010s, and have since plateaued. Freshwater communities downstream of dams, urban areas and cropland were less likely to experience recovery. Communities at sites with faster rates of warming had fewer gains in taxon richness, functional richness and abundance. Although biodiversity gains in the 1990s and 2000s probably reflect the effectiveness of water-quality improvements and restoration projects, the decelerating trajectory in the 2010s suggests that the current measures offer diminishing returns. Given new and persistent pressures on freshwater ecosystems, including emerging pollutants, climate change and the spread of invasive species, we call for additional mitigation to revive the recovery of freshwater biodiversity.

While many efforts have been devoted to understand variations in food web structure among terrestrial and aquatic ecosystems, the environmental factors influencing food web structure at large spatial scales remain hardly explored. Here, we compiled biodiversity inventories to infer food web structure of 67 French lakes using an allometric niche-based model and tested how environmental variables (temperature, productivity, and habitat) influence them. By applying a multivariate analysis on 20 metrics of food web topology, we found that food web structural variations are represented by two distinct complementary and independent structural descriptors. The first is related to the overall trophic diversity, whereas the second is related to the vertical structure. Interestingly, the trophic diversity descriptor was mostly explained by habitat size (26.7% of total deviance explained) and habitat complexity (20.1%) followed by productivity (dissolved organic carbon: 16.4%; nitrate: 9.1%) and thermal variations (10.7%). Regarding the vertical structure descriptor, it was mostly explained by water thermal seasonality (39.0% of total deviance explained) and habitat depth (31.9%) followed by habitat complexity (8.5%) and size (5.5%) as well as annual mean temperature (5.6%). Overall, we found that temperature, productivity, and habitat characteristics collectively shape lake food web structure. We also found that intermediate levels of productivity, high levels of temperature (mean and seasonality), as well as large habitats are associated with the largest and most complex food webs. Our findings, therefore, highlight the importance of focusing on these three components especially in the context of global change, as significant structural changes in aquatic food webs could be expected under increased temperature, pollution, and habitat alterations.

Abstract The underlying mechanisms of acquired resistance to the immune checkpoint inhibitory (ICI) PD-1 and PD-L1 antibodies remain largely unknown and need to be further explored. In this study, we established and analyzed robust ICI resistance in in vivo models in order to identify new mechanisms and genes involved in acquired resistance. Resistant in vivo models were obtained by serial treatment/reimplantation cycles in immunocompetent mice bearing MC38, MB49, MBT2, TyrNRas or RENCA tumors. Spectral cytometry was applied to characterize modifications in the tumor immune microenvironment. RNAseq analyses were performed to identify differences in gene expression profiles between sensitive parental models compared to their resistant counterparts. Alterations in the tumor immune microenvironment were highly heterogeneous amongst resistant models, and are thus considered representative for the diversity expected in patients. Each resistant model displayed multiple modifications in the tumor immune infiltrate in comparison to the respective wild type model, involving selected lymphoid and/or myeloid subpopulations. For instance, in anti-PD-1 and anti-PD-L1 resistant MC38 models, we observed a remarkable increase of FoxP3+CD4+ T cells while CD8+ Tem cells were decreased in anti PD-1 resistant models. We also found that the type 2 macrophage content was increased in the anti PD-1 resistant MB49 model. Gene profiling analyses demonstrated the variability associated with acquisition of a resistance phenotype. Alterations of pathways previously reported to be associated with resistance to ICIs were observed in some of our models while other genes appeared to be highly de-regulated in several models. For instance, in the anti PD-L1 resistant MBT2 model many signaling pathways were found to be up-regulated, such as HIF1α, TGFβ, and ERK/MAPK signaling. Several therapeutic combinations, in particular targeting alternative immune checkpoints, were found to reverse the resistance phenotype in selected models. Moreover, in accordance with flow cytometry results, in the anti PD-1 resistant MC38 model we observed a significant delay in tumor growth when a TNFR1 antibody was combined with a PD-1 antibody (p<0.001). Acquired in vivo resistant models displayed strong diversity, both in terms of alterations of the tumor immune microenvironment and tumor gene expression profiles. Our model library, which may be enriched in the future with several other variants developed using the same methodology, provides an innovative tool to better understand the complexity and diversity of resistance to ICI and test resistance reversal strategies. Citation Format: Morgane Denis, Chloé Grasselly, Pierre-Antoine Choffour, Anne Wierinckx, Doriane Mathé, Kamel Chettab, Anne Tourette, Nolan Talhi, Fabian Birzele, Elsa Kress, Lars Petter Jordheim, Christian Klein, Eva-Laure Matera, Charles Dumontet. Characterization of acquired resistant models to therapies targeting the PD-1/PD-L1 axis demonstrates model-dependent mechanisms [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 4200.

Abstract BACKGROUND: Metastatic colorectal cancer (mCRC) is one of the major causes of death worldwide. The relative therapeutic resistance of these populations to I/O drives the need for new treatment. STC-1010 (Brenus Pharma) therapeutic vaccine is developed by tumor cells stimulation to induce overexpression of TAA and neoantigens to mimic mCRC resistant cancer cells allowing education of the immune system to target the patient’s tumor cells harboring the same resistance factors. We report results of a study evaluating efficacy and safety of a 3 cell lines-based product namely “3CL-SH” (made of CT26, CMT93 and LTPA) physical stimulated (S=irradiation and heat shock) and haptenized (H) with immunostimulant in an anti-PD1 resistant MC38 colorectal tumor model grafted with its TME. METHODS: Female C57BL/6 mice bearing MC38 tumor model grown in vivo under anti-PD1 selection pressure (anti-PD1; 12.5 mg/kg; qw) to obtain MC38 resistant to anti-PD1 treatment (MC38 antiPD1R). Two sampled tumors from these mice were cut into fragment of 2 mm2 and reimplanted in the right flank of naïve syngenic mice. 5 groups (15 mice per group) were allocated to: G1) Control group: Isotype/placebo/vehicle G2) Anti-PD1/placebo/vehicule G3) Anti PD1/placebo-GM-CSF/endoxan G4) Isotype/3CL-SH-GM-CSF/endoxan G5) Anti-PD1/3CL-SH-GM-CSF/endoxan. Endoxan, vehicule and antibodies were administered by IP, vaccine or placebo subcutaneously. Overall survival (OS) and tumour growth (TG) were recorded until 1600 mm3 or safety endpoint. 5 mice per group were euthanized and sampled for immunophenotyping. In parallel, we conducted the identification and relative quantification of proteins expressed in 3CL-SH by LC-MS/MS and flow cytometry. RESULTS: Flow cytometry analysis shows that HSP-70 expression was significantly upregulated in each of the three cell lines of the 3CL-SH compared to untreated cells. LC-MS/MS analysis demonstrated that cell lines of 3CL-SH display overexpression of membrane proteins of interest such as Lamp 1, MDR1A/B and Fas Receptor. The group treated with 3CL-SH significantly improves the survival of mice bearing MC38PD1R tumor model vs the control group (Log-rank Mantel-Cox test, pvalue=0.0368) and we observed a non-benefit of the combination of 3CL-SH and anti-PD1 drug in concomitant injections. The immunophenotyping data show statistical increase in the infiltration of anti-tumor populations (CD8+ T cells, M1) in the tumors treated with 3CL-SH but also an increase in M2. No side effect or inflammatory reaction towards the 3CL-SH is evidenced. CONCLUSION: The 3CL-SH treatment presents a promising antitumor efficacy on the aggressive MC38 PD1R model, resulting in a significative gain of survival and anti-tumoral changes in the immune infiltrate of treated animals. More studies are needed to evaluate the benefit of a combination with ICI. Citation Format: Céline Gongora, Elsa Kress, Claudine Vermot-Desroches, Lionel Chalus, Jeremy Forget, Benoît Pinteur, Paul Bravetti, Charles Dumontet, Antoîne Italiano. Antitumor activity of a novel allogeneic colorectal cancer vaccine in C57BL/6 mice bearing MC38 anti-PD1 resistant colon carcinoma syngeneic model with TME [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 2051.

Tropical Andean glaciers are retreating rapidly, with possible consequences for trophic structure and ecosystem processes in high Andean meltwater streams. Here, we measured the environmental characteristics, quantified pools of particulate organic matter (POM) and periphyton (Chl. a), sampled benthic macroinvertebrates, determined functional feeding groups (FFG), and performed mesh bag decomposition experiments with Calamagrostis grass detritus at 17 stream sites along a gradient of glacial influence (GI) with 0–23% glacier cover in the catchment at 4050–4200 m a.s.l. in the Andes of Ecuador. POM was unrelated to GI while Chl. a. showed a weak (non-significant) negative relationship to GI. The macrofauna abundance decreased while taxon richness and the number of FFGs per site showed a hump-shaped relationship with increasing GI. Taxa with an opportunistic and generalist feeding mode generally dominated benthic assemblages and were related to high GI levels and low Chl. a. Only shredders were negatively related to GI, but unrelated to POM. Decomposition rates were comparable to those found in temperate alpine streams, and for both fine (0.0010–0.0065; median 0.0028 d−1) and coarse (0.0019–0.0088; median 0.0048 d−1) mesh bags, peaked at intermediate GI values, while the difference between bag types was small and almost constant along the GI gradient. This indicates an overall minor effect of macroinvertebrate shredders compared to that of microbes, in particular at high GI. It also suggests that the relatively high average temperature of these high-altitude equatorial streams (7–10 °C) does not produce higher decomposition rates than those in comparable but colder streams at temperate latitudes. The results suggest that, at the lower end of glacier cover, tropical glacier loss will not change the dominant microbial role in detritus decomposition, but that part of the physical abrasion could be partially replaced by biological shredding.