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Although the immune checkpoint function of PD-L1 has dominated its study, we report that PD-L1 has an unanticipated intrinsic function in promoting the dynamics of persistent cell migration. PD-L1 concentrates at the rear of migrating carcinoma cells where it facilitates retraction, resulting in the formation of PD-L1–containing retraction fibers and migrasomes. PD-L1 promotes retraction by interacting with and localizing the β4 integrin to the rear enabling this integrin to stimulate contractility. This mechanism involves the ability of PD-L1 to maintain cell polarity and lower membrane tension at the cell rear compared with the leading edge that promotes the localized interaction of PD-L1 and the β4 integrin. This interaction enables the β4 integrin to engage the actin cytoskeleton and promote RhoA-mediated contractility. The implications of these findings with respect to cell-autonomous functions of PD-L1 and cancer biology are significant.

Prostate cancers (PC) are largely unresponsive to immune checkpoint inhibitors and there is strong evidence that PD-L1 expression itself must be inhibited to activate anti-tumor immunity. Here, we report that neuropilin-2 (NRP2), which functions as a VEGF receptor on tumor cells, is an attractive target to activate anti-tumor immunity in prostate cancer because we demonstrate that VEGF/NRP2 signaling sustains PD-L1 expression. NRP2 depletion increased T cell activation in vitro and immune-mediated tumor elimination in vivo using a humanized mouse model. Inhibition of the binding of VEGF to NRP2 using a mouse specific anti-NRP2 mAb in a syngeneic model of prostate cancer that is resistant to checkpoint inhibition resulted in significant necrosis and tumor regression compared to control IgG. This therapy also decreased tumor PD-L1 expression and increased immune cell infiltration. We also observed that the NRP2 and VEGF-A genes are amplified in metastatic castration resistant and neuroendocrine prostate cancer (NEPC) and that NRP2high PD-L1high population in metastatic tumors had a significantly lower AR and higher NEPC scores than other populations. Therapeutic inhibition of VEGF binding to human NRP2 with a high affinity humanized mAb, which is suitable for clinical use, in organoids derived from NEPC patients also diminished PD-L1 expression and caused a significant increase in immune-mediated tumor cell killing consistent with the animal studies. These findings provide justification for the initiation of clinical trials using this novel function-blocking NRP2 mAb in prostate cancer, especially for patients with aggressive primary and metastatic cancers, where blocking NRP2-VEGF signaling shows potential in mitigating the morbidity and mortality associated with these cancers. Citation Format: Mengdie Wang, Christi A Wisniewski, Choua Xiong, Peter Chhoy, Hira Goel, Zhiwen Xu, Massimo Loda, Zhong Jiang, Michael Brehm, Arthur Mercurio. Therapeutic blocking of VEGF binding to Neuropilin-2 diminishes PD-L1 expression to activate anti-tumor immunity in prostate cancer [abstract]. In: Proceedings of the AACR Special Conference: Tumor Immunology and Immunotherapy; 2022 Oct 21-24; Boston, MA. Philadelphia (PA): AACR; Cancer Immunol Res 2022;10(12 Suppl):Abstract nr A44.

At the crossroads of political turmoil, statelessness, and globalization, Palestinian American youth negotiate their sense of a transnational belonging and citizenship as Palestinians and Americans...

Whether framed as model minorities or used as evidence that the model minority is a myth, Hmong Americans and other Southeast Asians are constrained by the model minority stereotype. As a disciplinary tool, the model minority stereotype controls Asian American experiences and identities. This paper explores the complex and diverse ways that Hmong Americans in a community in Wisconsin are making sense of and responding to the model minority stereotype and the racial positioning of the Hmong American community. Our paper will illustrate the persistent power of the model minority stereotype to frame Asian American experiences, identities and actions.

Adipocyte fatty acid binding protein-4 (FABP4) is a 132-aa intracellular lipid binding protein involved in the transport of fatty acids between cell membranes and organelles. FABP4 participates in several pathways including lipolysis and lipogenesis, and is involved in lipid and energy metabolism related diseases such as diabetes. Although the x-ray structure of FABP4 has been determined and binding to several of its hydrophobic ligands well characterized, the transitions in the structural dynamics upon ligand binding has yet to be determined. Here, solution NMR experiments will be carried out on 15N and 13C labeled FABP4 to study the structural transitions between its free and bound states. Spin relaxation measurements will also be used to reveal any changes that occur upon binding of FABP4 to its hydrophobic ligands.

Phospholamban (PLN) is the endogenous inhibitor of the sarco(endo)plasmic reticulum Ca2+-ATPase (SERCA), the enzyme that regulates cardiac muscle relaxation. In its phosphorylated state (pS16-PLN, pT17-PLN, and pS16pT17-PLN), PLN does not inhibit SERCA. Dysfunctions in SERCA:PLN interactions and in the PLN phosphorylation mechanism have been implicated in cardiac disease, and targeting PLN is becoming a promising avenue for treating cardomyopathies. In this study, we seek to further improve the design therapeutic PLN mutants by optimizing their functional interactions with an endogenous regulatory phosphatase of PLN, protein phosphatase-1 (PP1). PP1 is responsible for PLN dephosphorylation and the transition from its non-inhibitory to inhibitory state. Using a combination of NMR spectroscopy and biochemical assays, correlations will be built between the structural dynamics of promising therapeutic mutants of PLN and their ability to be dephosphorylated by PP1. Additionally, several new mutants of PLN are developed with the goal they will be able to partially inhibit SERCA and also be impervious to dephosphorylation. Insights to these issues will provide better paradigms with which to design therapeutic mutants of PLN for treatment of heart failure, and also demonstrate a model by which an enzyme can be controlled through tuning the allosteric regulation of an inhibitor.