Unveiling the secrets of snakes: Analysis of environmental, socioeconomic, and spatial factors associated with snakebite risk in Paraná, Southern Brazil.

The state of Paraná is home to three out of the five medically significant snake genera in Brazil and lacks of snakebite epidemiology studies. This study aimed to ascertain the spatial, environmental, and socioeconomic factors associated with snakebite risk by analyzing notification data of cases in the state of Paraná. Notification and socioeconomic data were gathered from the online platforms of the National System of Notifiable Diseases (SINAN) and the Brazilian Institute of Geography and Statistics (IBGE). Land cover and land use maps were obtained from the Mapbiomas platform in raster format and subsequently converted into vectors using QGis software. The proportions of land use and land cover in square kilometers (km2) were then calculated. All acquired data were tabulated using Microsoft Excel 365 software. For spatial analysis, GeoDa software version 1.20 was utilized to calculate the Global and Local Moran indices, assessing spatial correlations. Between 2007 and 2021, 12,877 notifications were recorded, with an average incidence of 8.22/100,000 inhabitants in the state, 8166 (63.41%) caused by Bothrops, 1534 (11.91%) caused by Crotalus, 56 (0.43%) caused by Micrurus. 1703 (13.22%) caused by non-venomous snake species, and the remaining cases did not have the identified causative species. The incidents caused by Bothrops and Crotalus showed different distribution patterns. Spatial analysis revealed that key factors contributing to snakebite risk included the presence of native forests, mangroves, apicuns, and monospecific planted forests. The population group at the highest risk comprised rural residents and workers. Furthermore, the absence of basic sanitation and proper garbage collection and disposal exhibited positive correlations with snakebites. Conversely, intensive farming practices with substantial mechanization and pastures demonstrated negative spatial correlations. This study has enabled the identification of the primary factors associated with snakebite risk, facilitating more targeted efforts to prevent snakebite accidents among vulnerable populations.

A neutrophil response linked to tumor control in immunotherapy.

Neutrophils accumulate in solid tumors, and their abundance correlates with poor prognosis. Neutrophils are not homogeneous, however, and could play different roles in cancer therapy. Here, we investigate the role of neutrophils in immunotherapy, leading to tumor control. We show that successful therapies acutely expanded tumor neutrophil numbers. This expansion could be attributed to a Sellhi state rather than to other neutrophils that accelerate tumor progression. Therapy-elicited neutrophils acquired an interferon gene signature, also seen in human patients, and appeared essential for successful therapy, as loss of the interferon-responsive transcription factor IRF1 in neutrophils led to failure of immunotherapy. The neutrophil response depended on key components of anti-tumor immunity, including BATF3-dependent DCs, IL-12, and IFNγ. In addition, we found that a therapy-elicited systemic neutrophil response positively correlated with disease outcome in lung cancer patients. Thus, we establish a crucial role of a neutrophil state in mediating effective cancer therapy.

Macrophage-Targeted Therapy Unlocks Antitumoral Cross-talk between IFNγ-Secreting Lymphocytes and IL12-Producing Dendritic Cells.

Macrophages often abound within tumors, express colony-stimulating factor 1 receptor (CSF1R), and are linked to adverse patient survival. Drugs blocking CSF1R signaling have been used to suppress tumor-promoting macrophage responses; however, their mechanisms of action remain incompletely understood. Here, we assessed the lung tumor immune microenvironment in mice treated with BLZ945, a prototypical small-molecule CSF1R inhibitor, using single-cell RNA sequencing and mechanistic validation approaches. We showed that tumor control was not caused by CSF1R+ cell depletion; instead, CSF1R targeting reshaped the CSF1R+ cell landscape, which unlocked cross-talk between antitumoral CSF1R- cells. These cells included IFNγ-producing natural killer and T cells, and an IL12-producing dendritic cell subset, denoted as DC3, which were all necessary for CSF1R inhibitor-mediated lung tumor control. These data indicate that CSF1R targeting can activate a cardinal cross-talk between cells that are not macrophages and that are essential to mediate the effects of T cell-targeted immunotherapies and promote antitumor immunity.See related Spotlight by Burrello and de Visser, p. 4.

Resident Kupffer cells and neutrophils drive liver toxicity in cancer immunotherapy.

Immunotherapy is revolutionizing cancer treatment but is often restricted by toxicities. What distinguishes adverse events from concomitant antitumor reactions is poorly understood. Here, using anti-CD40 treatment in mice as a model of TH1-promoting immunotherapy, we showed that liver macrophages promoted local immune-related adverse events. Mechanistically, tissue-resident Kupffer cells mediated liver toxicity by sensing lymphocyte-derived IFN-γ and subsequently producing IL-12. Conversely, dendritic cells were dispensable for toxicity but drove tumor control. IL-12 and IFN-γ were not toxic themselves but prompted a neutrophil response that determined the severity of tissue damage. We observed activation of similar inflammatory pathways after anti-PD-1 and anti-CTLA-4 immunotherapies in mice and humans. These findings implicated macrophages and neutrophils as mediators and effectors of aberrant inflammation in TH1-promoting immunotherapy, suggesting distinct mechanisms of toxicity and antitumor immunity.