Intelligent Biomimetic Nanoplatform for Systemic Treatment of Metastatic Triple-Negative Breast Cancer via Enhanced EGFR-Targeted Therapy and Immunotherapy.

Triple-negative breast cancer (TNBC) is the most malignant subtype of breast cancer, and it is associated with a high recurrence rate, metastatic potential, and poor prognosis. Thus, effective therapeutic strategies for TNBC are urgently required. The epidermal growth factor receptor (EGFR) is considered to be a potential therapeutic target for TNBC. However, there are limitations to the use of targeted therapies, such as afatinib (AFT), particularly drug resistance. Here, we investigated a poly(d,l-lactide-glycolide) (PLGA)-based intelligent bionic nanoplatform, termed AFT/2-BP@PLGA@MD, which combined targeted therapy with immunotherapy. In this platform, PLGA was used to encapsulate 2-bromo-palmitate (2-BP), a palmitoylation inhibitor, to enhance the efficacy of AFT against TNBC cells. PLGA was coated with a cancer cell membrane anchored with a cleavable peptide by matrix metalloproteinase-2 to block programmed cell death protein 1 (PD-1)/programmed death ligand 1 (PD-L1). 2-BP significantly enhanced the capacity of AFT to inhibit the proliferation and migration of tumor cells in vitro. Moreover, the tumor cell membrane-coated AFT/2-BP@PLGA@MD nanoparticles exhibited enhanced tumor targeting ability in vivo. The AFT/2-BP@PLGA@MD nanoparticles significantly inhibited the growth and metastasis of 4T1 tumor and prolonged the survival of tumor-bearing mice. The nanoparticles also triggered antitumor immune response. Collectively, we report an effective therapeutic strategy for clinically refractory TNBC.

Interleukin-36α inhibits colorectal cancer metastasis by enhancing the infiltration and activity of CD8+ T lymphocytes.

Colorectal cancer is one of the deadliest cancers, and the discovery of new diagnostic biomarkers and therapeutic targets is vital. Interleukin-36α (IL-36α) is a proinflammatory factor that can initiate the inflammatory response and promote the systemic T helper-1 (Th1) immune response. In this study, we investigated the immunological role of IL-36α in CRC. We found that IL-36α was downregulated in human CRC tissues. Patients with high IL-36α levels showed better survival and low IL-36α expression was significantly associated with greater tumor distal metastasis and TNM stage. We constructed two cell lines overexpressing IL-36α (CT26-IL-36α and HT29-IL-36α cells). In vitro assays revealed that IL-36α overexpression reduced the proliferation, migration, and invasion of CT26-IL-36α, and HT29-IL-36α cells. Using CT26-vector and CT26-IL-36α tumor mouse model and lung metastasis models, we found that IL-36α overexpression elicited a significant antitumor effect and inhibited lung metastasis in vivo. These inhibitory effects were associated with an increase in the number of CD3+CD8+ T lymphocytes within the tumor tissue as well as increased cytokine production in CD8+ T lymphocytes present in the tumor, spleen, and draining lymph nodes. Furthermore, we revealed that CT26-IL-36α cells enhanced the secretion of CXCL10 and CXCL11 from chemotactic CD8+ T lymphocytes, as compared with CT26-vector cells. Taken together, these results suggest that IL-36α is a promising therapeutic agent for targeting CRC by promoting the activation, proliferation, and tumor infiltration of T lymphocytes.

Hepatic transcriptional profiling response to fava bean-induced oxidative stress in glucose-6-phosphate dehydrogenase-deficient mice.

Favism is an acute hemolytic syndrome caused by the ingestion of fava bean (FB) in glucose 6-phosphate dehydrogenase (G6PD) deficient individuals. However, little is known about the global transcripts alteration in liver tissue after FB ingestion in G6PD-normal and -deficient states. In this study, deep sequencing was used to analyze liver genes expression alterations underlying the effects of FB in C3H (Wild Type, WT) and G6PD-deficient (G6PDx) mice and to evaluate and visualize the collective annotation of a list of genes to Gene Ontology (GO) terms associated with favism. Our results showed that FB resulted in a decrease of glutathione (GSH)-to-oxidized glutathione (GSSG) ratio and an increase of malondialdehyde (MDA) both in the G6PDx and WT-control check (CK) mice plasma. Significantly, liver transcript differences were observed between the control and FB-treated groups of both WT and G6PDx mice. A total of 320 differentially expressed transcripts were identified by comparison of G6PDx-CK with WT-CK and were associated with immune response and oxidation-reduction function. A total of 149 differentially expressed genes were identified by comparison of WT-FB with WT-CK. These genes were associated with immune response, steroid metabolic process, creatine kinase activity, and fatty acid metabolic process. A total of 438 differential genes were identified by comparing G6PDx-FB with G6PD-CK, associated with the negative regulation of fatty acid metabolic process, endoplasmic reticulum, iron binding, and glutathione transferase activity. These findings indicate that G6PD mutations may affect the functional categories such as immune response and oxidation-reduction.