Chimeric antigen receptor- and natural killer cell receptor-engineered innate killer cells in cancer immunotherapy

Chimeric antigen receptor(CAR)-engineered T-cell(CAR-T)therapy has demonstrated impressive therapeutic efficacy against hematological malignancies,but multiple challenges have hindered its application,particularly for the eradication of solid tumors.Innate killer cells(IKCs),particularly NK cells,NKT cells,andγδT cells,employ specific antigen-independent innate tumor recognition and cytotoxic mechanisms that simultaneously display high antitumor efficacy and prevent tumor escape caused by antigen loss or modulation.IKCs are associated with a low risk of developing GVHD,thus offering new opportunities for allogeneic“off-the-shelf”cellular therapeutic products.The unique innate features,wide tumor recognition range,and potent antitumor functions of IKCs make them potentially excellent candidates for cancer immunotherapy,particularly serving as platforms for CAR development.In this review,we first provide a brief summary of the challenges hampering CAR-T-cell therapy applications and then discuss the latest CAR-NK-cell research,covering the advantages,applications,and clinical translation of CAR-and NK-cell receptor(NKR)-engineered IKCs.Advances in synthetic biology and the development of novel genetic engineering techniques,such as gene-editing and cellular reprogramming,will enable the further optimization of IKC-based anticancer therapies.

NK cell receptor imbalance and NK cell dysfunction in HBV nfection and hepatocellular carcinoma

Hepatocellular carcinoma （HCC） is currently the third leading cause of cancer mortality and a common poor-prognosis malignancy due to postoperative recurrence and metastasis. There is a significant correlation between chronic hepatitis B virus （HBV） infection and hepatocarcinogenesis. As the first line of host defense against viral infections and tumors, natural killer （NK） cells express a large number of immune recognition receptors （NK receptors （NKRs）） to recognize ligands on hepatocytes, liver sinusoidal endothelial cells, stellate cells and Kupffer cells, which maintain the balance between immune response and immune tolerance of NK cells. Unfortunately, the percentage and absolute number of liver NK cells decrease significantly during the development and progression of HCC. The abnormal expression of NK cell receptors and dysfunction of liver NK cells contribute to the progression of chronic HBV infection and HCC and are significantly associated with poor prognosis for liver cancer. In this review, we focus on the role of NK cell receptors in anti-tumor immune responses in HCC, particularly HBV-related HCC. We discuss specifically how tumor cells evade attack from NK cells and how emerging understanding of NKRs may aid the development of novel treatments for HCC. Novel mono- and combination therapeutic strategies that target the NK cell receptor-ligand system may potentially lead to successful and effective immunotherapy in HCC.

Leukocyte driven-decidual angiogenesis in early.pregnancy

Successful pregnancy and long-term, post-natal maternal and offspring cardiac, vascular and metabolic health require key maternal cardiovascular adaptations over gestation. Within the pregnant decidualizing uterus, coordinated vascular, immunological and stromal cell changes occur. Considerable attention has been given to the roles of uterine natural killer （uNK） cells in initiating decidual spiral arterial remodeling, a process normally completed by mid-gestation in mice and in humans. However, leukocyte roles in much earlier, region specific, decidual vascular remodeling are now being defined. Interest in immune cell-promoted vascular remodeling is driven by vascular aberrations that are reported in human gestational complications such as infertility, recurrent spontaneous abortion, preeclampsia （PE） and fetal growth restriction. Appropriate maternal cardiovascular responses during pregnancy protect mothers and their children from later cardiovascular disease risk elevation. One of the earliest uterine responses to pregnancy in species with hemochorial placentation is stromal cell decidualization, which creates unique niches for angiogenesis and leukocyte recruitment. In early decidua basalis, the aspect of the implantation site that will cradle the developing placenta and provide the major blood vessels to support mature placental functions, leukocytes are greatly enriched and display specialized properties. UNK cells, the most abundant leukocyte subset in early decidua basalis, have angiogenic abilities and are essential for normal early decidual angiogenesis. The regulation of uNK cells and their roles in determining maternal and progeny cardiovascular health over ore^nancv and PostPartum are discussed.