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Despite advancements in targeting the immune checkpoints program cell death protein 1 (PD-1), programmed death ligand 1 (PD-L1), and cytotoxic T lymphocyte-associated protein 4 (CTLA-4) for cancer immunotherapy, a large number of patients and cancer types remain unresponsive. Current immunotherapies focus on modulating an antitumor immune response by directly or indirectly expanding antitumor CD8 T cells. A complementary strategy might involve inhibition of Tregs that otherwise suppress antitumor immune responses. Here, we sought to identify functional immune molecules preferentially expressed on tumor-infiltrating Tregs. Using genome-wide RNA-Seq analysis of purified Tregs sorted from multiple human cancer types, we identified a conserved Treg immune checkpoint signature. Using immunocompetent murine tumor models, we found that antibody-mediated depletion of 4-1BB-expressing cells (4-1BB is also known as TNFRSF9 or CD137) decreased tumor growth without negatively affecting CD8 T cell function. Furthermore, we found that the immune checkpoint 4-1BB had a high selectivity for human tumor Tregs and was associated with worse survival outcomes in patients with multiple tumor types. Thus, antibody-mediated depletion of 4-1BB-expressing Tregs represents a strategy with potential activity across cancer types., Introduction Immune checkpoint molecules are a group of surface proteins expressed on various immune cell subsets that can function as either stimulatory or inhibitory mediators, depending upon cell-specific and contextual [...]

Co-inhibitory immune receptors can contribute to T cell dysfunction in patients with cancer.sup.1,2. Blocking antibodies against cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) and programmed cell death 1 (PD-1) partially reverse this effect and are becoming standard of care in an increasing number of malignancies.sup.3. However, many of the other axes by which tumours become inhospitable to T cells are not fully understood. Here we report that V-domain immunoglobulin suppressor of T cell activation (VISTA) engages and suppresses T cells selectively at acidic pH such as that found in tumour microenvironments. Multiple histidine residues along the rim of the VISTA extracellular domain mediate binding to the adhesion and co-inhibitory receptor P-selectin glycoprotein ligand-1 (PSGL-1). Antibodies engineered to selectively bind and block this interaction in acidic environments were sufficient to reverse VISTA-mediated immune suppression in vivo. These findings identify a mechanism by which VISTA may engender resistance to anti-tumour immune responses, as well as an unexpectedly determinative role for pH in immune co-receptor engagement. V-domain immunoglobulin suppressor of T cell activation (VISTA) selectively engages P-selectin glycoprotein ligand-1 (PSGL-1) and suppresses T cells at acidic pH similar to those in tumour microenvironments, thereby mediating resistance to anti-tumour immune responses., Author(s): Robert J. Johnston [sup.1] , Linhui Julie Su [sup.2] , Jason Pinckney [sup.3] , David Critton [sup.4] , Eric Boyer [sup.1] , Arathi Krishnakumar [sup.5] , Martin Corbett [sup.6] [...]

Molluscan aquaculture is often promoted as an alternative to wild shellfisheries, yet expansion of growing areas is sometimes opposed by groups concerned with aesthetics and use conflicts. Amidst these conflicts, public preferences remain unquantified in rigorous terms. This article presents a discrete choice experiment that elicits preferences for large-scale molluscan aquaculture with different production technologies and impacts. Results for a Connecticut (US) case study show that willingness to pay (WTP) is heterogeneous, with the largest effects on preferences due to localized water clarity impacts and employment gains. Preferences vary over alternative locations for growing areas but are positive on average, suggesting widespread public support. Results suggest that policies aiming to optimize WTP for molluscan aquaculture expansion should allow aquaculture attributes to vary over locations, consistent with public preferences. [ABSTRACT FROM AUTHOR]

This paper examines empirically the importance of equity preferences for the formation of international environmental agreements (IEA) for transboundary pollution control. Although it has been shown theoretically that the existence of equity preferences among countries considering an IEA increases the chances for formation and stability of a coalition, empirical assessments of such preferences have been limited to climate change mitigation and single‐country studies. We consider the case of marine plastic pollution, of which a large share consists of food and beverage containers, representing a transboundary pollution control problem of increasing policy concern, with properties that lead to distinct considerations for equity and the sharing of abatement costs. We employ a coordinated choice experiment in the United Kingdom and United States to assess preferences for abatement‐cost allocations in a marine plastics IEA. Pairs of cooperating countries and the relative allocation of abatement costs are varied experimentally. Results show systematic aversion to both advantageous and disadvantageous inequality with respect to abatement costs but also that the relative strength of advantageous and disadvantageous inequality aversion differs across countries. Across both countries, there is evidence that left‐leaning voters generally favor more equal international sharing of abatement costs. Differences of these results from the case of greenhouse gas emission reduction, and implications for current efforts to establish a legally binding global treaty on marine plastic pollution, are discussed. [ABSTRACT FROM AUTHOR]