Immunosuppression of tumor-infiltrating lymphocytes (TIL) is a common feature of advanced cancer, but its biological basis has remained obscure. We demonstrate here a molecular link between epithelial-to-mesenchymal transition (EMT) and CD8+ TIL immunosuppression, two key drivers of cancer progression. We show that microRNA-200 (miR-200), a cell-autonomous suppressor of EMT and metastasis, targets PD-L1. Moreover, ZEB1, an EMT activator and transcriptional repressor of miR-200, relieves miR-200 repression of PD-L1 on tumor cells, leading to CD8+ T cell immunosuppression and metastasis. These findings are supported by robust correlations between the EMT score, miR-200 levels and PD-L1 expression in multiple human lung cancer datasets. In addition to revealing a link between EMT and T cell dysfunction, these findings also show that ZEB1 promotes metastasis through a heretofore unappreciated cell non-autonomous mechanism, and suggest that subgroups of patients in whom malignant progression is driven by EMT activators may respond to treatment with PD-L1 antagonists.

Although treatment with immune checkpoint inhibitors provides promising benefit for patients with cancer, optimal use is encumbered by high resistance rates and requires a thorough understanding of resistance mechanisms. We observed that tumors treated with PD-1/PD-L1 blocking antibodies develop resistance through the upregulation of CD38, which is induced by all-trans retinoic acid and IFNβ in the tumor microenvironment. and studies demonstrate that CD38 inhibits CD8 T-cell function via adenosine receptor signaling and that CD38 or adenosine receptor blockade are effective strategies to overcome the resistance. Large data sets of human tumors reveal expression of CD38 in a subset of tumors with high levels of basal or treatment-induced T-cell infiltration, where immune checkpoint therapies are thought to be most effective. These findings provide a novel mechanism of acquired resistance to immune checkpoint therapy and an opportunity to expand their efficacy in cancer treatment. CD38 is a major mechanism of acquired resistance to PD-1/PD-L1 blockade, causing CD8 T-cell suppression. Coinhibition of CD38 and PD-L1 improves antitumor immune response. Biomarker assessment in patient cohorts suggests that a combination strategy is applicable to a large percentage of patients in whom PD-1/PD-L1 blockade is currently indicated. .

The rapid development of artificial intelligence techniques and future advanced robot systems sparks emergent demand on the accurate perception and understanding of the external environments via visual sensing systems that can co-locate the self-adaptive detecting, processing, and memorizing of optical signals. In this contribution, a simple indium–tin oxide/Nb-doped SrTiO3 (ITO/Nb:SrTiO3) heterojunction artificial optoelectronic synapse is proposed and demonstrated. Through the light and electric field co-modulation of the Schottky barrier profile at the ITO/Nb:SrTiO3 interface, the oxide heterojunction device can respond to the entire visible light region in a neuromorphic manner, allowing synaptic paired-pulse facilitation, short/long-term memory, and “learning-experience” behavior for optical information manipulation. More importantly, the photoplasticity of the artificial synapse has been modulated by heterosynaptic means with a sub-1 V external voltage, not only enabling an optoelectronic analog of the mechanical aperture device showing adaptive and stable optical perception capability under different illuminating conditions but also making the artificial synapse suitable for the mimicry of interest-modulated human visual memories.

A trilayer single-crystalline GDY film on graphene was prepared through a solution-phase van der Waals epitaxial strategy.