Targeting of IL-10R on acute myeloid leukemia blasts with chimeric antigen receptor-expressing T cells.

Acute myeloid leukemia (AML) is a biologically and clinically heterogeneous disease with a dismal prognosis and limited treatment options. Chimeric antigen receptor (CAR) T cells have achieved unprecedented clinical responses in patients with B cell malignancies but a dismal consequences in AML. In our previous study, we found that interleukin-10 receptor (IL-10R) was overexpressed in most AML cells, and played an important role in promoting the stemness of leukemia cells. In this study, we developed a novel ligand-based CAR-T cell targeting IL-10R, which displayed striking cytotoxicity both in vitro and in vivo against AML cells. Except for monocytes, it had no significant adverse effects on the normal hematopoietic system, including CD34+ hematopoietic stem and progenitor cells (HSPCs). In addition, even though the incorporation of IL-10 in the CAR cassette led to phenotypes change, it had few adverse effects on the survival and biological activity of IL-10 CAR-T cells and did not cause excessive proliferation of leukemia cells. Therefore, we propose IL-10R is a novel promising therapeutic candidate for AML, and IL-10R targeted CAR-T therapy provides a new treatment strategy to improve the prognosis of AML.

Interleukin-10-regulated tumour tolerance in non-small cell lung cancer.

BACKGROUND: Lung cancer is the most life-threatening cancer type worldwide. Treatment options include surgery, radio- and chemotherapy, as well as the use of immunomodulatory antibodies. Interleukin (IL)-10 is an immunosuppressive cytokine involved in tumour immune escape. METHODS: Immunohistochemistry (IHC) on human lung surgery tissue as well as human tumour cell line cultures, FACS analysis, real-time PCR and experimental lung cancer. RESULTS: Here we discovered a positive correlation between IL-10 and IL-10 receptor (IL-10R) expression in the lung with tumour diameter in patients with lung cancer (non-small cell lung cancer), the most life-threatening cancer type worldwide. IL-10 and IL-10R were found induced in cells surrounding the lung tumour cells, and IL-10R was mainly expressed on the surface of Foxp-3+ T-regulatory lymphocytes infiltrating the tumour of these patients where its expression inversely correlated with programmed cell death 1. These findings were confirmed in translational studies. In a human lung adenocarcinoma cell line, IL-10R was found induced under metabolic restrictions present during tumour growth, whereby IL-10 inhibited PDL1 and tumour cell apoptosis. CONCLUSIONS: These new findings suggest that IL-10 counteracts IFN-γ effects on PD1/PDL1 pathway, resulting in possible resistance of the tumour to anti-PD1/PDL1 immunotherapy.

Expression of IL-10 and IL-10 receptors on peripheral blood lymphocytes and monocytes in human head and neck squamous cell carcinoma.

OBJECTIVE: Interleukin-10 (IL-10) can mediate anti-tumor activity or tumor escape from the immune system. Here, we investigate IL-10 and IL-10recepter (IL-10R) expression in/on immune cells of patients with head and neck squamous cell carcinoma (HNSCC) and healthy volunteers as normal controls (NC) to further evaluate the dual role IL-10 might play in this disease. METHODS: Peripheral blood mononuclear cells from 15 HNSCC patients and 15 NC were stained and used for flow cytometry or stimulated first with OKT3/anti-CD28 Abs in the presence of IL-2 or with lipopolysaccharide and then stained for flow cytometry. The percentages of IL-10+ or IL-10R+ lymphocytes and monocytes and their mean fluorescence intensity were determined. RESULTS: Monocytes had the highest frequency of IL-10+ and IL-10R+ cells before or after stimulation and the highest expression levels of these markers followed by CD8+ and then CD4+ T lymphocytes. No significant differences in the frequency or expression levels of IL-10 or IL-10R were observed between patients with HNSCC and NC. CONCLUSIONS: Monocytes in the circulation of patients and NC are the main subset of IL-10- and IL-10R-expressing cells. The frequency of IL-10+ and IL-10R+ monocytes in patients with HNSCC is comparable to that in NC.

Oral glucocorticoid treatment decreases interleukin-10 receptor expression on peripheral blood leucocyte subsets.

Glucocorticoids (GCS) are capable of stimulating the secretion of interleukin (IL)-10 by leucocytes; however, the potential of GCS to modulate leucocyte susceptibility to IL-10-mediated actions has not yet been studied. In the current paper, we performed a detailed cross-sectional analysis of IL-10 receptor (IL-10R) expression by CD4(+) and CD8(+) T cells, natural killer (NK) cells, monocytes and neutrophils. Next, we analysed the effects of short-term oral GCS treatment on surface IL-10R expression by various leucocyte subpopulations in asthmatic patients. All leucocyte subsets studied presented with substantial levels of surface IL-10R. The highest levels of IL-10R were found on monocytes, predominantly with CD14(2+)CD16(+) and CD14(+)CD16(+) phenotypes, and on CD4(+)CD25(high) T cells. In contrast, levels of IL-10R on CD8(+) T cells, NK cells and neutrophils were significantly lower and similar to each other in intensity. GCS treatment resulted in a significant decrease of IL-10R expression on all analysed peripheral blood leucocyte subsets. Our data suggest that down-regulation of IL-10R could counterbalance the otherwise suppressive action of GCS.