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. .

Neuroblastoma (NB) is the most common malignant tumor in infancy and most common extracranial solid tumor in childhood. With the improvement of diagnosis and treatment, the survival rate of patients with low-risk and intermediate-risk NB can reach up to 90%. In contrast, for high-risk NBs, the long-term survival rate is still <40% because of heterogeneity of this tumor. The pathogenesis of NB is still not explicit, therefore it is of great significance to explore the mechanism of NB tumorigenesis and discover new therapeutic targets for NB. Polo-like kinase 4 (PLK4), one of the polo-like kinase family members, is an important regulator of centriole replication. The aberrant expression of PLK4 was found in several cancers and a recent study has unraveled a novel function of PLK4 as a mediator of invasion and metastasis in Hela and U2OS cells. However, the function of PLK4 in NB development and progression remains to be elucidated. The study showed the expression level of PLK4 in NB tissues was remarkably upregulated and high expression of PLK4 was negatively correlated with clinical features and survival, which suggested that PLK4 could be a potential tumor-promoting factor of NB. Functional studies indicated downregulation of PLK4 suppressed migration and invasion and promoted apoptosis in NB cells. Further experiments showed that downregulation of PLK4 in NB cells inhibited EMT through the PI3K/Akt signaling pathway. Animal experiments demonstrated that the downregulation of PLK4 in SK-N-BE(2) cells dramatically suppressed tumorigenesis and metastasis. PLK4 may be a promising therapeutic target for NB.

Tissue engineering has long been investigated to repair articular cartilage defects. Successful reports have usually involved the seeding of autologous chondrocytes into polymers. Problems arise because of the scarcity of cartilage tissue biopsy material, and because the in vitro expansion of chondrocytes is difficult; to some extent, these problems limit the clinical application of this promising method. Bone marrow-derived mesenchymal stem cells (MSCs) have been proved a potential cell source because of their in vitro proliferation ability and multilineage differentiation capacity. However, in vitro differentiation will lead to high cost and always results in decreased cell viability. In this study we seeded culture-expanded autologous MSCs into bioceramic scaffold-beta-tricalcium phosphate (beta-TCP) in an attempt to repair articular cartilage defects (8 mm in diameter and 4 mm in depth) in a sheep model. Twenty-four weeks later, the defects were resurfaced with hyaline-like tissue and an ideal interface between the engineered cartilage, the adjacent normal cartilage, and the underlying bone was observed. From 12 to 24 weeks postimplantation, modification of neocartilage was obvious in the rearrangement of surface cartilage and the increase in glycosaminoglycan level. These findings suggest that it is feasible to repair articular cartilage defects with implants generated by seeding autologous MSCs, without in vitro differentiation, into beta-TCP. This approach provides great potential for clinical applications.

At present, the most popular biomaterials used in cartilage tissue engineering are synthetic polymers. However, problems-such as acidic by-product accumulation and side effects in local or systemic inflammatory reactions during in vivo degradation-are drawing much attention. The polymers are also highly hydrophobic and degrade within 4 weeks, allowing insufficient time to support neocartilage formation. All these have made polymers less promising in clinical application. In this study, we tested a new bioceramic scaffold made of artificial synthesized powder of beta-tricalcium phosphate (beta-TCP) in a sheep model. Osteochondral defects were filled with a bioceramic-chondrocyte construct and neocartilage tissue completely resurfaced the cartilage defects after 24 weeks. Typical hyaline cartilage structure was generated in the engineered cartilage. Biodegradation of bioceramic was notable, leading to bioceramic fragmentation and particle formation. Numerous ceramic particles (size, 0.5-1.9 microm) and numerous macrophages were observed at the ceramic-tissue interface as well as in the marrow tissue. No macrophages were visible in the neocartilage tissue. Although long-term in vivo study is needed to further determine the pathological sequences of the beta-TCP-based cartilage construct, this study suggests that this bioceramic might be used to repair chondral or osteochondral defects and could be used as a scaffold for cartilage tissue engineering.