Excessive and persistent inflammation after injury lead to chronic wounds, increased tissue damage or even aggressive carcinogenic transformation. Effective wound repair could be achieved by inhibiting overactive immune cells to the injured site. In this study, we obtained high concentration of PD-L1 in exosomes from either genetically engineered cells overexpressing PD-L1 or IFN-γ stimulated cells. We found that exosomal PD-L1 is specially bound to PD-1 on T cell surface, and suppressed T cell activation. Interestingly, exosomal PD-L1 promoted the migration of epidermal cells and dermal fibroblasts when pre-incubated with T cells. We further embedded exosomes into thermoresponsive PF-127 hydrogel, which was gelatinized at body temperature to release exosomes to the surroundings in a sustained manner. Of importance, in a mouse skin excisional wound model, exosomal PD-L1 significantly fastened wound contraction and reepithelialization when embedded in hydrogel during inflammation phase. Finally, exosomal PD-L1 inhibited cytokine production of CD8+ T cells and suppressed CD8+ T cell numbers in spleen and peripheral lymph nodes. Taken together, these data provide evidence on exosomal PD-L1 exerting immune inhibitory effects and promoting tissue repair.

T cell activation by immune allorecognition is a major contributing factor toward the triggering of organ rejection. Immunosuppressive drugs have to be taken after organ transplantation, but long-term use of these drugs increases the risks of infection and other serious disorders. Here, we showed dysregulation of programmed cell deathligand 1/programmed cell death 1 (PD-L1/PD-1) and cytotoxic T-lymphocyte-associated protein 4/cluster of differentiation 80 (CTLA-4/CD80) in the spleen of two organ transplantation models. Using a bioengineering approach, cellular exosome-like nanovesicles (NVs) displaying PD-L1/CTLA-4 dual-targeting cargos were designed, and their specificity to bind their ligands PD-1 and CD80 on T cell and dendritic cell surfaces was confirmed. These NVs consequently enhanced PD-L1/PD-1 and CTLA-4/CD80 immune inhibitory pathways, two key immune checkpoints to co-inhibit T cell activation and maintain peripheral tolerance. It was also confirmed that PD-L1/ CTLA-4 NVs led to the reduction of T cell activation and proliferation in vitro and in vivo. Finally, it was demonstrated that PD-L1/CTLA-4 NVs reduced density of CD8 + T cells and cytokine production, enriched regulatory T cells, and prolonged the survival of mouse skin and heart grafts. Taken together, these data supported the idea that PD-L1/CTLA-4 dual-targeting NVs exert immune inhibitory effects and may be used as a prospective immunosuppressant in organ transplantation.

ISRCTN Registry (Retrospectively registered; Reference number: 35067; Date: 02/04/2018).

Objective: To evaluate the comparative therapeutic efficacy of radiofrequency ablation (RFA) and hepatic resection (HR) for breast cancer liver metastases (BCLMs). Methods: Studies that had examined the outcomes for both RFA and HR for BCLM were identified by searching the electronic databases PubMed, EMBASE, and the Cochrane Library. Pooled analyzes of the overall survival (OS), disease-free survival (DFS), and short-term outcomes of BCLM were performed. Results: Patients with BCLM gained many more survival benefits from HR than from RFA with regard to the 3-year OS rate (combined odds ratio (OR) 0.41, 95% confidence interval (CI) 0.29-0.59, P<0.001), 5-year OS rate (combined OR 0.38, 95% CI 0.32-0.46, P<0.001), 3-year DFS (combined OR 0.36, 95% CI 0.27-0.49, P<0.001), and 5-year DFS (combined OR 0.51, 95% CI 0.40-0.66, P<0.001). RFA had fewer postoperative complications (combined OR 0.30, 95% CI 0.20-0.44, P<0.001) and shorter hospital stays (combined OR −9.01, 95% CI −13.49-4.54, P<0.001) than HR. Conclusions: HR takes precedence over RFA in the treatment of patients with BCLM, considering the better survival rate. RFA gives rise to fewer complications and can be carried out with a shorter hospital stay, compared to HR. RFA should be reserved for patients who are not optimum candidates for resection.

Effective treatments for patients suffering from heat hypersensitivity are lacking, mostly due to our limited understanding of the pathogenic mechanisms underlying this disorder. In the nervous system, activating transcription factor 4 (ATF4) is involved in the regulation of synaptic plasticity and memory formation. Here, we show that ATF4 plays an important role in heat nociception. Indeed, loss of ATF4 in mouse dorsal root ganglion (DRG) neurons selectively impairs heat sensitivity. Mechanistically, we show that ATF4 interacts with transient receptor potential cation channel subfamily M member-3 (TRPM3) and mediates the membrane trafficking of TRPM3 in DRG neurons in response to heat. Loss of ATF4 also significantly decreases the current and KIF17-mediated trafficking of TRPM3, suggesting that the KIF17/ATF4/TRPM3 complex is required for the neuronal response to heat stimuli. Our findings unveil the non-transcriptional role of ATF4 in the response to heat stimuli in DRG neurons.