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Endocrine therapy is considered as an effective strategy for estrogen and progestogen receptor (ER and PR)-positive breast cancer (BRCA) patients, whereas resistance to these agents is the major cause of BRCA mortality in women. Immune checkpoint receptor (ICR) blockade is another approach to treat BRCA, but the response rate of this approach for non-triple-negative breast cancer (non-TNBC) is relatively low. Recently, the androgen receptor (AR) has been identified as a tumor suppressor in ER-positive BRCA; however, the relationship between the levels of androgens and ICRs on T cells in BRCA is unclear. We observed that testosterone and dihydrotestosterone (DHT) in patients with HER2 and Luminal B were significantly lower than those in healthy controls, and the expression of AR has significant correlation with overall survival (OS) advantage for Luminal B patients. Moreover, testosterone and DHT were positively correlated with the PD-1 expression on Vδ1+ T cells in HER2 and Luminal B patients. These results suggest a potential approach of combining androgens with PD-1 blockade for treating HER2 and Luminal B breast cancer.

Epidemiological surveys have revealed that low serum vitamin D level was correlated with increased risk of tumors. Dysfunctional T cells in patients with tumor are characterized as exhausted with high levels of immune checkpoint receptors (ICRs). However, whether the reduced level of vitamin D in patients with cancer correlates with cytotoxic T-cell exhaustion is unknown.Periphery blood samples from 172 patients with non-small cell lung cancer (NSCLC) were prospectively collected. Patients with NSCLC received one course of intravenous docetaxel (75 mg/mWe show that serum level of vitamin D is negatively correlated with expression of programmed cell death-1 (PD-1), T-cell immunoreceptor with Ig and ITIM domains (TIGIT), and T-cell immunoglobulin and mucin-domain containing-3 (Tim-3), but positively correlated with CD28 expression on CD8Our findings uncover the pleiotropic effects of 1α,25(OH)ChiCTR2100051135.

Triple-negative breast cancer (TNBC) escape from immune-mediated destruction was associated with immunosuppressive responses that dampened the activation of tumor-infiltrating CD8 and γδ T cells. TNBC had a higher level of programmed cell death 1-ligand 1 (PD-L1) and indoleamine 2,3-dioxygenase (IDO), compared with other breast cancer subtypes. But, clinical studies have revealed that the response rate of PD-1/PD-L1 antibody for TNBC treatment was relatively low. However, the antitumor responses of human Vγ9Vδ2 T cells or IDO inhibitor in TNBC treatment are unknown. In this study, we found that IDO1 and PD-L1 were highly expressed in TNBC patients. Analysis of the clinical samples demonstrated that Vγ9Vδ2 T cells became exhausted in triple-negative breast cancer patients. And Vγ9Vδ2 T cells combined with αPD-L1 could not further enhance their antitumor responses in vitro and in vivo. However, Vγ9Vδ2 T cells combined with IDO1 inhibitor 1-Methyl-L-tryptophan (1-MT) or Lindrostat showed substantial inhibitory effects on MDA-MB-231 tumor cells. Finally, we found that IDO1 inhibitor promoted T cell’s cytotoxicity by enhancing perforin production. These results converged to suggest the potential application of Vγ9Vδ2 T cells treated with IDO1 inhibitor for TNBC therapy.

Neonicotinoid insecticides (NEOs) are widely used for pest control worldwide. The profile of NEOs in paired urine and indoor dust has not yet been reported in China. In this study, 40 paired samples (i.e., 160 urine and 40 indoor dust) were collected from university students and dormitories from Guangzhou City of China to measure the concentrations of six NEOs and their three metabolites. Target analytes were frequently detected in paired urine (81%-98%) and indoor dust (75%-95%) samples, with median concentrations ranging from 0.02 [specific gravity (SG) adjusted: 0.02] to 2.08 (SG-adjusted: 2.38) ng/mL in urine and from 0.05 to 2.74 ng/g in indoor dust. 5-Hydroxy-imidacloprid was predominant in urine, while N-desmethyl acetamiprid was predominant in indoor dust samples, accounting for 56% and 37%, respectively. 1-Methyl-3-(tetrahydro-3-furylmethyl) urea, a dinotefuran degradate, was measured for the first time in indoor dust, with the median level of 1.02 ng/g. Significant gender-related differences (p 0.05) in the urinary concentrations of most NEOs were found. We calculated the estimated daily intake (EDI) of target compounds from urine and indoor measurements. The EDIs of target analytes varied among all urine and indoor dust samples, with median values ranging from 0.51 (SG-adjusted: 0.56) to 51.6 (SG-adjusted: 52.8) ng/kg bw/day and from 0.04 to 2.10 pg/kg bw/day, respectively. Moreover, the median EDIs

Additional file 5:. Supplementary Information: text summary

Additional file 6:. Supplementary table 1. mNSS protocols

Epidemiological surveys have revealed that low serum vitamin D level was correlated with increased risk of tumors. Dysfunctional T cells in tumor patients are characterized as exhausted with high levels of immune checkpoint receptors (ICRs). However, whether the reduced level of vitamin D in cancer patients correlates with cytotoxic T cell exhaustion is unknown. Here, we show that serum level of vitamin D is negatively correlated with expression of PD-1, TIGIT, and Tim-3, but positively correlated with CD28 expression on CD8+ and Vγ9Vδ2+ T cells in patients with non-small cell lung cancer (NSCLC). 1α,25(OH)2D3, the active form of vitamin D, promotes the nuclear translocation of vitamin D receptor (VDR), which binds to the promoter region of Pdcd1, Tim3, Tigit genes and inhibits their expression. Besides, 1α,25(OH)2D3 pretreatment also promotes the methylation of CpG island in promoter region of Pdcd1 gene and increases H3K27 acetylation at promoter region of Cd28 gene, which leads to surface PD-1 down-regulation and CD28 up-regulation respectively. We further reveal that VDR-mediated Ca2+ influx enhanced expression of Th1 cytokines via T cell receptor activation. Functionally, 1α,25(OH)2D3 pretreated CD8+ T cells or Vγ9Vδ2+ T cells showed increased Th1 cytokines production and enhanced anti-tumor immunity. Finally, oral 1α,25(OH)2D3 could also decrease expression of PD-1, Tim-3, TIGIT and increase expression of CD28, resulting in cytokine production (associated with antitumor immunity) by cytotoxic T cells of patients with NSCLC. Collectively, our findings uncover the pleiotropic effects of 1α,25(OH)2D3 in rescuing exhausted phenotype of human cytotoxic T cells in tumor patients and promoting their anti-tumor immunity.

BackgroundEpidemiological surveys have revealed that low serum vitamin D level was correlated with increased risk of tumors. Dysfunctional T cells in patients with tumor are characterized as exhausted with high levels of immune checkpoint receptors (ICRs). However, whether the reduced level of vitamin D in patients with cancer correlates with cytotoxic T-cell exhaustion is unknown.MethodsPeriphery blood samples from 172 patients with non-small cell lung cancer (NSCLC) were prospectively collected. Patients with NSCLC received one course of intravenous docetaxel (75 mg/m2) followed by treatment with or without rocaltrol at a dose of 0.5–2.0 µg/day for total of 3 weeks. We performed phenotypical and functional analysis of T-cell through flow cytometry. Vitamin D receptor (VDR) knockout and overexpression CD8+ and Vδ2+ T cells were constructed using Cas9-gRNA targeted and overexpressing approaches to identify 1α,25(OH)2D3/VDR-mediated transcription regulation for ICRs or antitumor activity in T cells.ResultsWe show that serum level of vitamin D is negatively correlated with expression of programmed cell death-1 (PD-1), T-cell immunoreceptor with Ig and ITIM domains (TIGIT), and T-cell immunoglobulin and mucin-domain containing-3 (Tim-3), but positively correlated with CD28 expression on CD8+ and Vγ9Vδ2+ T cells in patients with NSCLC. 1α,25(OH)2D3, the active form of vitamin D, promotes the nuclear translocation of VDR, which binds to the promoter region of Pdcd1, Tim3, and Tigit genes and inhibits their expression. Besides, 1α,25(OH)2D3 pretreatment also promotes the methylation of CpG island in the promoter region of the Pdcd1 gene and increases H3K27 acetylation at the promoter region of the Cd28 gene, which leads to surface PD-1 downregulation and CD28 upregulation, respectively. We further reveal that VDR-mediated Ca2+ influx enhanced expression of Th1 cytokines via T-cell receptor activation. Functionally, 1α,25(OH)2D3 pretreated CD8+ T cells or Vγ9Vδ2+ T cells showed increased Th1 cytokine production and enhanced antitumor immunity. Finally, oral 1α,25(OH)2D3 could also decrease expression of PD-1, Tim-3, TIGIT and increase expression of CD28, resulting in cytokine production (associated with antitumor immunity) by cytotoxic T cells of patients with NSCLC.ConclusionsOur findings uncover the pleiotropic effects of 1α,25(OH)2D3 in rescuing the exhausted phenotype of human cytotoxic T cells in patients with tumor and in promoting their antitumor immunity.Trial registration numberChiCTR2100051135.

An intelligent moving agent (IMA) group designed for a mobile host (MH) is presented. The concept of group communication, intelligence and moving code are introduced into the design of the IMA. By the operation of the IMA group, a MH can act as a computer on the wired network and the following goals can be achieved: (1) the MH on the wireless network can become a member on the internet; (2) the hand-off problem can be solved by the moving feature of an IMA; (3) the location problem can also be solved by introducing the concept of group communication among the IMAs, which resides on different base stations, serving the same MH; and (4) the reliability and bandwidth of wireless communication can be solved by the store and forward ability of the IMA.