Abnormal expression of activating/inhibitory receptors leads to natural killer (NK) cells dysfunction in tumor. Here we show that programmed cell death protein 1 (PD-1), a well-known immune checkpoint of T cells, is highly expressed on peripheral and tumor-infiltrating NK cells from patients with digestive cancers including esophageal, liver, colorectal, gastric and biliary cancer. The increased PD-1 expression on NK cells indicates poorer survival in esophageal and liver cancers. Blocking PD-1/PD-L1 signaling markedly enhances cytokines production and degranulation and suppresses apoptosis of NK cells in vitro. PD-1/PD-L1 exerts inhibitory effect through repressing the activation of PI3K/AKT signaling in NK cells. More importantly, a PD-1 blocking antibody was found to significantly suppress the growth of xenografts in nude mice, and this inhibition of tumor growth was completely abrogated by NK depletion. These findings strongly suggested that PD-1 is an inhibitory regulator of NK cells in digestive cancers. PD-1 blockade might be an efficient strategy in NK cell-based tumor immunotherapy.

The imbalance of immune status in cancer microenvironment plays an important role in the development and progression of cancer. Immunotherapy based on this has become an important field of cancer research in recent years. Many studies on long noncoding RNA (lncRNA) in cancer have focus on its regulation in cancer development and metastasis. Recent studies have suggested that lncRNAs play crucial roles in different phases of cancer immunity, including antigen releasing, antigen presentation, immune activation, immune cells migration, infiltrating into cancer tissues, and killing cancer cells. The functional studies of lncRNAs in cancer immuntity revealed the complicated molecular mechanisms in cancer immunity from a new point of view, which may provide novel potential targets for cancer immunotherapies. Based on the classical cancer-immunity cycle theory, we review the recent studies on the functions and mechanisms of immune-related lncRNAs in different stages of cancer immunity, to summarize the relationship between lncRNAs, and cancer immunity and to provide a framework for further research.

Owing to its easy-to-use and multiplexing nature, the genome editing tool CRISPR-Cas9 (clustered regularly interspaced short palindromic repeats (CRISPR) associated nuclease 9) is revolutionizing many areas of medical research and one of the most amazing areas is its gene therapy potentials. Previous explorations into the therapeutic potentials of CRISPR-Cas9 were mainly conducted in vitro or in animal germlines, the translatability of which, however, is either limited (to tissues with adult stem cells amenable to culture and manipulation) or currently impermissible (due to ethic concerns). Recently, important progresses have been made on this regard. Several studies have demonstrated the ability of CRISPR-Cas9 for in vivo gene therapy in adult rodent models of human genetic diseases delivered by methods that are potentially translatable to human use. Although these recent advances represent a significant step forward to the eventual application of CRISPR-Cas9 to the clinic, there are still many hurdles to overcome, such as the off-target effects of CRISPR-Cas9, efficacy of homology-directed repair, fitness of edited cells, immunogenicity of therapeutic CRISPR-Cas9 components, as well as efficiency, specificity, and translatability of in vivo delivery methods. In this article, we introduce the mechanisms and merits of CRISPR-Cas9 in genome editing, briefly retrospect the applications of CRISPR-Cas9 in gene therapy explorations and highlight recent advances, later we discuss in detail the challenges lying ahead in the way of its translatability, propose possible solutions, and future research directions.

Background Effective treatment for breast cancer-related chronic lymphedema (bcrl) remains a clinical challenge.

◥Natural killer (NK) cells are enriched within the liver. Apart from conventional NK (cNK) cells, recent studies identified a liverresident NK (LrNK) subset, which constitutes about half of hepatic NK cells and exhibits distinct developmental, phenotypic, and functional features. However, it remains unclear whether and how LrNK cells, as well as cNK cells, participate in the development of hepatocellular carcinoma (HCC) individually. Here, we report that both LrNK and cNK cells are significantly decreased in HCC. The T-cell immunoglobulin and mucin domain-containing protein 3 (Tim-3) was significantly upregulated in both tumor-infiltrating LrNK and cNK cells and suppressed their cytokine secretion and cytotoxic activity. Mechanistically, phosphatidylserine (PtdSer) engagement promoted phosphorylation of Tim-3, which then competed with PI3K p110 to bind p85, inhibiting downstream Akt/mTORC1 signaling and resulting in malfunctioning of both NK-cell subsets. Tim-3 blockade retarded HCC growth in a NKcell-dependent manner. These studies for the first time report the presence and dysfunction of LrNK cells in HCC and show that Tim-3-mediated PI3K/mTORC1 interference is responsible for the dysfunction of both tumor-infiltrating cNK and LrNK cells, providing a new strategy for immune checkpoint-based targeting.Significance: Tim-3 enhances hepatocellular carcinoma growth by blocking natural killer cell function.