Morphostructural Characterization of the Heterogeneous Rhodolith Bed at the Marine Protected Area “Capo Carbonara” (Italy) and Hydrodynamics

Mediterranean rhodolith beds are priority marine benthic habitats for the European Community, because of their relevance as biodiversity hotspots and their role in the carbonate budget. Presently, Mediterranean rhodolith beds typically occur within the range of 30–75 m of water depth, generally located around islands and capes, on flat or gently sloping areas. In the framework of a collaboration between the University of Milano-Bicocca and the Marine Protected Area “Capo Carbonara” (Sardinia, Italy), video explorations and sampling collections in three selected sites revealed the occurrence of a well developed and heterogeneous rhodolith bed. This bed covers an area >41 km2 around the cape, with live coverage ranging between 6.50 and 55.25%. Rhodoliths showed interesting morphostructural differences. They are small compact pralines at the Serpentara Island, associated with gravelly sand, or bigger boxwork at the Santa Caterina shoal associated with sand, whereas branches are reported mostly in the Is Piscadeddus shoal, associated with muddy sand. Both in the Santa Caterina shoal and the Serpentara Island, rhodoliths generally show a spheroidal shape, associated with a mean value of currents of 4.3 and 7.3 cm/s, respectively, up to a maximum of 17.7 cm/s at Serpentara, whereas in the Is Piscadeddus shoal rhodolith shape is variable and current velocity is significantly lower. The different hydrodynamic regime, with a constant current directed SW, which deviates around the cape towards E, is responsible for such morphostructural heterogeneity, with the site of the Serpentara Island being the most exposed to a constant unidirectional and strong current. We can associate current velocity with specific rhodolith morphotypes. The morphostructural definition of the heterogeneity of rhodoliths across large beds must be considered for appropriate management policies

Downregulation of Membrane Trafficking Proteins and Lactate Conditioning Determine Loss of Dendritic Cell Function in Lung Cancer

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A population of TIM4+FOLR2+ macrophages localized in tertiary lymphoid structures correlates to an active immune infiltrate across several cancer types

TIM4 has previously been associated with antitumor immunity, yet the pattern of expression and the function of this receptor across human cancer tissues remains poorly explored. Here we combined extensive immunolabeling of human tissues with in-silico analysis of pan-cancer transcriptomic datasets to explore the clinical significance of TIM4 expression. Our results unveil that TIM4 is expressed on a fraction of cavity macrophages (CATIM4+MΦ) of carcinoma patients. Moreover, we uncover a high expression of TIM4 on macrophages of the T-cell zone of the carcinoma-associated tertiary lymphoid structures (TLSTIM4+MΦ). In-silico analysis of a pan-cancer dataset revealed a positive correlation between TIM4 expression and markers of B cells, effector CD8+ T cells and a 12-chemokine signature defining tertiary lymphoid structure. In addition, TLSTIM4+MΦ were enriched in cancers displaying microsatellite instability and high CD8+ T-cell infiltration, confirming their association with immune-reactive tumors. Both CATIM4+MΦ and TLSTIM4+MΦ express FOLR2, a marker of tissue-resident MΦ. However, CATIM4+MΦ had higher expression of the immunosuppressive molecules TREM2, IL10 and TGFβ as compared to TLSTIM4+MΦ. By analyzing a scRNA-seq dataset of tumor-associated myeloid cells we identified two TIM4+FOLR2+ clusters coherent with CATIM4+MΦ and TLSTIM4+MΦ. We defined specific gene-signatures for each subset and found that the CATIM4+ MΦ signature was associated with worse patient survival. In contrast, TLSTIM4+MΦ gene-signature positively correlate with better prognosis. Together these data illustrate that TIM4 marks two distinct macrophage populations with distinct phenotype and tissue localization and that may have opposing roles in tumor immunity

Laser Therapy Inhibits Tumor Growth in Mice by Promoting Immune Surveillance and Vessel Normalization

Laser therapy, recently renamed as photobiomodulation, stands as a promising supportive treatment for oral mucositis induced by oncological therapies. However, its mechanisms of action and, more importantly, its safety in cancer patients, are still unclear. Here we explored the anti-cancer effect of 3 laser protocols, set at the most commonly used wavelengths, in B16F10 melanoma and oral carcinogenesis mouse models. While laser light increased cell metabolism in cultured cells, the in vivo outcome was reduced tumor progression. This striking, unexpected result, was paralleled by the recruitment of immune cells, in particular T lymphocytes and dendritic cells, which secreted type I interferons. Laser light also reduced the number of highly angiogenic macrophages within the tumor mass and promoted vessel normalization, an emerging strategy to control tumor progression. Collectively, these results set photobiomodulation as a safety procedure in oncological patients and open the way to its innovative use for cancer therapy

Wiskott-Aldrich syndrome protein restricts cGAS/STING activation by dsDNA immune complexes

International audienceDysregulated sensing of self–nucleic acid is a leading cause of autoimmunity in multifactorial and monogenic diseases. Mutations in Wiskott-Aldrich syndrome protein (WASp), a key regulator of cytoskeletal dynamics in immune cells, cause autoimmune manifestations and increased production of type I IFNs by innate cells. Here we show that immune complexes of self-DNA and autoantibodies (DNA-ICs) contribute to elevated IFN levels via activation of the cGAS/STING pathway of cytosolic sensing. Mechanistically, lack of endosomal F-actin nucleation by WASp caused a delay in endolysosomal maturation and prolonged the transit time of ingested DNA-ICs. Stalling in maturation-defective organelles facilitated leakage of DNA-ICs into the cytosol, promoting activation of the TBK1/STING pathway. Genetic deletion of STING and STING and cGAS chemical inhibitors abolished IFN production and rescued systemic activation of IFN-stimulated genes in vivo. These data unveil the contribution of cytosolic self–nucleic acid sensing in WAS and underscore the importance of WASp-mediated endosomal actin remodeling in preventing innate activation

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

International audienceCross-presentation by type 1 DCs (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) remain unclear. Here we develop a hypermutated model of non-small cell lung cancer in female mice, encoding genuine MHC-I neoepitopes to study neoAgs-specific CD8 T cell responses in spontaneous settings and upon Flt3L + αCD40 (DC-therapy). We find that cDC1 are required to generate broad CD8 responses against a range of diverse neoAgs. DC-therapy promotes immunogenicity of weaker neoAgs and strongly inhibits the growth of high tumor-mutational burden (TMB) tumors. In contrast, low TMB tumors respond poorly to DC-therapy, generating mild CD8 T cell responses that are not sufficient to block progression. scRNA transcriptional analysis, immune profiling and functional assays unveil the changes induced by DC-therapy in lung tissues, which comprise accumulation of cDC1 with increased immunostimulatory properties and less exhausted effector CD8 T cells. 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