Proteogenomic characterization of pancreatic ductal adenocarcinoma.

Pancreatic ductal adenocarcinoma (PDAC) is a highly aggressive cancer with poor patient survival. Toward understanding the underlying molecular alterations that drive PDAC oncogenesis, we conducted comprehensive proteogenomic analysis of 140 pancreatic cancers, 67 normal adjacent tissues, and 9 normal pancreatic ductal tissues. Proteomic, phosphoproteomic, and glycoproteomic analyses were used to characterize proteins and their modifications. In addition, whole-genome sequencing, whole-exome sequencing, methylation, RNA sequencing (RNA-seq), and microRNA sequencing (miRNA-seq) were performed on the same tissues to facilitate an integrated proteogenomic analysis and determine the impact of genomic alterations on protein expression, signaling pathways, and post-translational modifications. To ensure robust downstream analyses, tumor neoplastic cellularity was assessed via multiple orthogonal strategies using molecular features and verified via pathological estimation of tumor cellularity based on histological review. This integrated proteogenomic characterization of PDAC will serve as a valuable resource for the community, paving the way for early detection and identification of novel therapeutic targets.

Synergistic combination of targeted nano-nuclear-reactors and anti-PD-L1 nanobodies evokes persistent T cell immune activation for cancer immunotherapy.

BACKGROUND: Antitumor T cell immunotherapy as a novel cancer therapeutic strategy has shown enormous promise. However, the tumor microenvironment (TME) is characterized by the low immunogenicity, hypoxia, and immunosuppressive condition that dramatically limit effective T cell immunotherapy. Thus, an ideal immunotherapy strategy that is capable of reversing the immunosuppressive TME is highly imperative. RESULTS: In this article, we reported that Fe-doped and doxorubicin (DOX) loaded HA@Cu2-XS-PEG (PHCN) nanomaterials were rationally designed as targeted Fe-PHCN@DOX nano-nuclear-reactors, which evoked persistent T cell immune response together with anti-PD-L1 nanobodies. It was confirmed that nano-nuclear-reactors displayed strong nanocatalytic effect for effective antitumor effects. Consequently, they maximized the immunogenic cell death (ICD) effect for antigen presentation and then stimulated T cell activation. In addition, Fe-PHCN@DOX could reprogram M2-phenotype tumor-associated macrophages (TAMs) into M1-phenotype TAMs by relieving tumor hypoxia. Meanwhile, blockade of the anti-PD-L1 nanobody promoted T cell activation through targeting the PD-1/PD-L1 immunosuppressive pathway. Notably, in vivo tumor therapy verified that this nano-nuclear-reactor could be used as an excellent immunotherapy nanoplatform for tumor eradication and metastasis prevention with nanobody. CONCLUSIONS: Our findings demonstrated that nano-nuclear-reactors in combination with nanobody could evoke persistent T cell immune activation, suggesting them potential as a promising immunotherapy option for reversing immunosuppressive immune-cold tumors.

Tumor immune microenvironment (TIME) to enhance antitumor immunity.

The tumor microenvironment is a result of dynamic interaction between different cellular and non-cellular components. In its essence it is not a solo performer, but an ensemble of performers that includes cancer cells, fibroblasts, myo-fibroblasts, endothelial cells and immune cells. The short review highlights important immune infiltrates within the tumor microenvironment that shape cytotoxic t lymphocyte (CTL)-rich immune hot and CTL-deficient immune cold tumors and novel strategies that have potential role in enhancing our immune responses in both immune hot and immune cold tumors.