Despite the remarkable success of chimeric antigen receptor (CAR)-T cells against hematologic malignancies, severe off-tumor effects have constrained their use against solid tumors. Recently, CAR-engineered natural killer (NK) cells have emerged as an effective and safe alternative. Here, we demonstrate that HER2 CAR-expression in NK cells from healthy donors and patients with breast cancer potently enhances their anti-tumor functions against various HER2-expressing cancer cells, regardless of MHC class I expression. Moreover, HER2 CAR-NK cells exert higher cytotoxicity than donor-matched HER2 CAR-T cells against tumor targets. Importantly, unlike CAR-T cells, HER2 CAR-NK cells do not elicit enhanced cytotoxicity or inflammatory cytokine production against non-malignant human lung epithelial cells with basal HER2 expression. Further, HER2 CAR-NK cells maintain high cytotoxic function in the presence of immunosuppressive factors enriched in solid tumors. These results show that CAR-NK cells may be a highly potent and safe source of immunotherapy in the context of solid tumors.
© 2021 The Authors.

Natural killer (NK) cells are useful for cancer immunotherapy and have proven clinically effective against hematologic malignancies. However, immunotherapies for poor prognosis solid malignancies, including ovarian cancer, have not been as successful due to immunosuppression by solid tumors. Although rearming patients' own NK cells to treat cancer is an attractive option, success of that strategy is limited by the impaired function of NK cells from cancer patients and by inhibition by self-MHC. In this study, we show that expansion converts healthy donor and immunosuppressed ovarian cancer patient NK cells to a cytotoxic CD56superbrightCD16+ subset with activation state and antitumor functions that increase with CD56 brightness. We investigated whether these expanded NK cells may overcome the limitations of autologous NK cell therapy against solid tumors. Peripheral blood- and ascites-derived NK cells from ovarian cancer patients were expanded and then adoptively transferred into cell-line and autologous patient-derived xenograft models of human ovarian cancer. Expanded ovarian cancer patient NK cells reduced the burden of established tumors and prolonged survival. These results suggest that CD56bright NK cells harbor superior antitumor function compared with CD56dim cells. Thus, NK cell expansion may overcome limitations on autologous NK cell therapy by converting the patient's NK cells to a cytotoxic subset that exerts a therapeutic effect against autologous tumor. These findings suggest that the value of expanded autologous NK cell therapy for ovarian cancer and other solid malignancies should be clinically assessed. Cancer Immunol Res; 6(10); 1174-85. ©2018 AACR.
©2018 American Association for Cancer Research.

The aim of the present study was to evaluate the efficacy of endoscopic ultrasound-guided fine-needle aspiration (EUS-FNA) in diagnosing mediastinal and intra-abdominal lymphadenopathies. A total of 154 patients with mediastinal and intra-abdominal lymphadenopathies were included in this retrospective study between February 2010 and March 2015. Malignancy was suspected in the patients as a result of imaging findings and EUS-FNAs were performed to confirm the diagnoses. EUS and EUS-FNA data, as well as hospital medical records, were reviewed. The accuracy of EUS-FNA was 90.8% for diagnosing malignancy and 85.6% for diagnosing benign lymphadenopathy. In combination with flow cytometry (FCM), the accuracy of EUS-FNA to determine lymphoma was 94.2%. Among the malignant lymphadenopathy cases, 80 were caused by metastasis, 19 by lymphoma and 1 by myeloid leukemia. In the 53 benign cases, EUS-FNA revealed a nonspecific inflammatory condition in 27 patients, tuberculosis in 21 patients and Castleman's disease in 5 patients. The factors revealed to be associated with malignant lymphadenopathy included the sex and age of patients, as well as the location and size of the enlarged lymph node. In particular, celiac axis lymphadenopathy was associated with malignancy (23.0% of cases of malignancy, vs. 3.8% of benign lymphadenopathy). EUS-FNA results additionally suggested that the malignant lymph nodes observed in celiac axis were more likely to result from lymphoma (42.1%; 8/19 cases) than metastasis (18.8%; 15/80 cases; P=0.039). By contrast, malignant lymph nodes observed in the mediastinum were more likely to be caused by metastasis (47.5%; 38/80 cases) than lymphoma (10.5%; 2/19 cases; P=0.004). The results of the present study suggested that EUS-FNA is accurate for differentiating between malignancy and benign lymphadenopathy. Therefore, EUS-FNA in combination with FCM analysis, as a minimally invasive and highly sensitive tool, should be routinely performed for the identification of lymphoma. Additionally, examining the enlarged celiac axis lymph nodes of elderly males, who exhibit an increased risk of malignancy, may be beneficial.

The development of maternal tolerance to the fetal allograft in critical for the maintenance of the pregnancy, and it is accompanied by the development of a special decidual natural killer (dNK) cell tolerance phenotype. To understand the factors that influence dNK cells during early pregnancy, the present study aimed to identify mesenchymal stem cells (MSCs) from human first‑trimester deciduas, termed decidual MSCs (DMSCs), and to investigate the effect of DMSCs on the regulation of dNK cells via collagen. Decidual samples were collected from women with normal pregnancy that had undergone elective vaginal surgical terminations at 6‑9 weeks gestation. DMSCs derived from human decidual tissues were cultured under differentiation conditions to examine their multipotent differentiation capacities, and the expression of MSC‑specific markers, including cluster of differentiation (CD)44, CD73, CD105, CD90, CD34, CD31, CD14, CD45, CD11b and human leukocyte antigen‑antigen D related, was determined. dNK cells were co‑cultured with DMSCs in order to examine the effect of DMSCs on the tolerance phenotype of dNK cells. The expression of cell surface molecules, natural cytotoxicity triggering receptor 3 and killer cell immunoglobulin‑like receptor (KIR) 2DL1, and the secretion of cytokines, including interferon‑γ, tumor necrosis factor (TNF)‑α, interleukin (IL)‑10, IL‑4 and perforin, were examined by flow cytometry analysis. To determine whether the regulation of dNK cells by DMSCs was mediated by collagen, DMSCs were pre‑treated with human recombinant leukocyte‑associated immunoglobulin‑like receptor (LAIR)‑2 and transfected with pScoR‑GFP‑hP4H to inhibit the interaction between LAIR‑1 and collagen. The present results demonstrated that collagen produced by DMSCs increased the expression of KIR2DL1 and IL‑4, decrease the expression of NKp30 and TNF‑α. In conclusion, the results of the present study demonstrated that DMSCs may be cultured in vitro for prolonged periods, whilst retaining the ability to differentiate into different cell lineages. In addition, DMSCs may modulate the function of dNK cells via the interaction between collagen and LAIR‑1.