Natural killer (NK) cells are cytotoxic group 1 innate lymphoid cells (ILC), known for their role as killers of stressed, cancerous, and virally infected cells. Beyond this cytotoxic function, NK cell subsets can influence broader immune responses through cytokine production and have been linked to central roles in non-immune processes, such as the regulation of vascular remodeling in pregnancy and cancer. Attempts to exploit the anti-tumor functions of NK cells have driven the development of various NK cell-based therapies, which have shown promise in both pre-clinical disease models and early clinical trials. However, certain elements of the tumor microenvironment, such as elevated transforming growth factor (TGF)-β, hypoxia, and indoalemine-2,3-dioxygenase (IDO), are known to suppress NK cell function, potentially limiting the longevity and activity of these approaches. Recent studies have also identified these factors as contributors to NK cell plasticity, defined by the conversion of classical cytotoxic NK cells into poorly cytotoxic, tissue-resident, or ILC1-like phenotypes. This review summarizes the current approaches for NK cell-based cancer therapies and examines the challenges presented by tumor-linked NK cell suppression and plasticity. Ongoing efforts to overcome these challenges are discussed, along with the potential utility of NK cell therapies to applications outside cancer.

Placentation is one of the most important determinants for a successful pregnancy, and this is dependent on the process of trophoblast migration and invasion. Progesterone receptors (PGR) are critical effectors of progesterone (P4) signaling that is required for trophoblast migration and invasion conducive to a successful gestation. In immune complicated pregnancies, evidence has shown that abnormal placentation occurs because of aberrant expression of PGR. Therapeutic intervention with tacrolimus (FK506) was able to restore PGR expression and improve pregnancy outcomes in immune-complicated gestations; however, the exact mode of action of tacrolimus in assisting placentation is not clear. Here, we attempt to uncover the mode of action of tacrolimus by examining its effects on trophoblast invasion and migration in the human-derived extravillous trophoblast (EVT) cell line, the HTR-8/SVneo cells. Using a variety of functional assays, we demonstrated that low-dose tacrolimus (10 ng/mL) was sufficient to significantly (p < 0.001) stimulate the migration and invasion of the HTR-8/SVneo cells, inducing their cytosolic/nuclear progesterone receptor expression and activation, and modulating their Nitric Oxide (NO) production. Moreover, tacrolimus abrogated the suppressive effect of the NOS inhibitor Nω- Nitro-L-Arginine Methyl Ester (L-NAME) on these vital processes critically involved in the establishment of human pregnancy. Collectively, our data suggest an immune-independent mode of action of tacrolimus in positively influencing placentation in complicated gestations, at least in part, through promoting the migration and invasion of the first trimester extravillous trophoblast cells by modulating their NO production and activating their cytosolic/nuclear progesterone-receptors. To our knowledge, this is the first report to show that the mode of action of tacrolimus as a monotherapy for implantation failure is plausibly PGR-dependent.

The remodeling of uterine spiral arteries and subsequent placental formation are crucial for normal growth and development of the fetus. These processes are heavily dependent on the functioning of the extra-villous trophoblast cells and their ability to invade into the maternal decidual blood vessels. Reduced trophoblast invasion and shallow spiral artery remodeling can lead to a number of gestational complications including intrauterine growth restriction (IUGR). Therapeutic intervention with low dose immunosuppressant tacrolimus was able to prevent implantation failure and IUGR in obese and diabetic mice. Treatment with tacrolimus successfully aided in spiral artery modification that was conducive to a successful pregnancy. Further, tacrolimus has shown promise in restoring trophoblast cell functioning in the immortalized first trimester HTR8/SVneo extra-villous trophoblast cells cultured under preeclampsia-like conditions in vitro. However, the mode of action of tacrolimus has yet to be elucidated. Here we attempt to uncover the mode of action of tacrolimus by examining its effects on eNOS activity within the trophoblast cells. Cells were treated with tacrolimus (10 ng/mL), L-NAME (40 nM/mL) or a combination of both and subjected to analysis by several functional assays. The data obtained in this study is suggesting that L-NAME treatment has inhibitory effects on the levels of the pPGR, pSTAT3 and NO within the HTR8/SVneo cells. The use of low-dose tacrolimus abrogated the suppressive effect of L-NAME and restored the levels of the pPGR, pSTAT3, and NO within the cells.

The surgical management of thymic neoplasms includes open and minimally invasive approaches. Previous studies have compared these techniques, but application in practice remains varied. This systematic review and network meta-analysis (NMA) will adhere to the Preferred Reporting Items for Systematic Review and Meta-Analysis (PRISMA) checklist. MEDLINE, Embase, Cochrane Centrale and Scopus will be searched from inception to perform a systematic review, NMA and evidence appraisal using the Grading of Recommendations Assessment, Development and Evaluations and the Confidence in Network Meta-Analysis methodologies. Randomized controlled trials and cohort studies will be included. Full texts of any citation will be included if they assessed a minimum of two arms of any type of thymectomy technique, including open, video-assisted thoracoscopic surgery, or robotic-assisted thoracoscopic surgery thymectomy, for the treatment of thymic neoplasms such as thymoma, thymic carcinoma or thymic neuroendocrine tumors with or without myasthenia gravis. Studies assessing operative thymectomy techniques for benign disease will be excluded. Short- and long-term perioperative safety and oncologic outcomes will be compared between open versus video-assisted versus robotic-assisted thymectomy for the surgical management of thymic neoplasms. The Risk of Bias In Non-Randomized Studies—of Interventions tool will be used to assess the risk of bias in nonrandomized studies. We will conduct a frequentist fixed- and random-effects NMA using the graph theory approach for each outcome. Summary of odds ratios will be estimated for all dichotomous outcomes with their 95% confidence interval.

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