Planning for resilience: Incorporating scenario and model uncertainty and trade-offs when prioritizing management of climate refugia.

Climate change has become the greatest threat to the world's ecosystems. Locating and managing areas that contribute to the survival of key species under climate change is critical for the persistence of ecosystems in the future. Here, we identify 'Climate Priority' sites as coral reefs exposed to relatively low levels of climate stress that will be more likely to persist in the future. We present the first analysis of uncertainty in climate change scenarios and models, along with multiple objectives, in a marine spatial planning exercise and offer a comprehensive approach to incorporating uncertainty and trade-offs in any ecosystem. We first described each site using environmental characteristics that are associated with a higher chance of persistence (larval connectivity, hurricane influence, and acute and chronic temperature conditions in the past and the future). Future temperature increases were assessed using downscaled data under four different climate scenarios (SSP1 2.6, SSP2 4.5, SSP3 7.0 and SSP5 8.5) and 57 model runs. We then prioritized sites for intervention (conservation, improved management or restoration) using robust decision-making approaches that select sites that will have a benign climate under most climate scenarios and models. The modelling work is novel because it solves two important issues. (1) It considers trade-offs between multiple planning objectives explicitly through Pareto analyses and (2) It makes use of all the uncertainty around future climate change. Priority intervention sites identified by the model were verified and refined through local stakeholder engagement including assessments of local threats, ecological conditions and government priorities. The workflow is presented for the Insular Caribbean and Florida, and at the national level for Cuba, Jamaica, Dominican Republic and Haiti. Our approach allows managers to consider uncertainty and multiple objectives for climate-smart spatial management in coral reefs or any ecosystem across the globe.

Microbially driven TLR5-dependent signaling governs distal malignant progression through tumor-promoting inflammation.

The dominant TLR5(R392X) polymorphism abrogates flagellin responses in >7% of humans. We report that TLR5-dependent commensal bacteria drive malignant progression at extramucosal locations by increasing systemic IL-6, which drives mobilization of myeloid-derived suppressor cells (MDSCs). Mechanistically, expanded granulocytic MDSCs cause γδ lymphocytes in TLR5-responsive tumors to secrete galectin-1, dampening antitumor immunity and accelerating malignant progression. In contrast, IL-17 is consistently upregulated in TLR5-unresponsive tumor-bearing mice but only accelerates malignant progression in IL-6-unresponsive tumors. Importantly, depletion of commensal bacteria abrogates TLR5-dependent differences in tumor growth. Contrasting differences in inflammatory cytokines and malignant evolution are recapitulated in TLR5-responsive/unresponsive ovarian and breast cancer patients. Therefore, inflammation, antitumor immunity, and the clinical outcome of cancer patients are influenced by a common TLR5 polymorphism.

Ovarian cancer progression is controlled by phenotypic changes in dendritic cells.

We characterized the initiation and evolution of the immune response against a new inducible p53-dependent model of aggressive ovarian carcinoma that recapitulates the leukocyte infiltrates and cytokine milieu of advanced human tumors. Unlike other models that initiate tumors before the development of a mature immune system, we detect measurable anti-tumor immunity from very early stages, which is driven by infiltrating dendritic cells (DCs) and prevents steady tumor growth for prolonged periods. Coinciding with a phenotypic switch in expanding DC infiltrates, tumors aggressively progress to terminal disease in a comparatively short time. Notably, tumor cells remain immunogenic at advanced stages, but anti-tumor T cells become less responsive, whereas their enduring activity is abrogated by different microenvironmental immunosuppressive DCs. Correspondingly, depleting DCs early in the disease course accelerates tumor expansion, but DC depletion at advanced stages significantly delays aggressive malignant progression. Our results indicate that phenotypically divergent DCs drive both immunosurveillance and accelerated malignant growth. We provide experimental support for the cancer immunoediting hypothesis, but we also show that aggressive cancer progression after a comparatively long latency period is primarily driven by the mobilization of immunosuppressive microenvironmental leukocytes, rather than loss of tumor immunogenicity.