PD-1 inhibitor combined with apatinib modulate the tumor microenvironment and potentiate anti-tumor effect in mice bearing gastric cancer.

OBJECTIVE: To explore the effect of programmed death 1 (PD-1) inhibitor combined with apatinib on immune regulation and efficacy of the combined therapy in mice bearing gastric cancer (MBGC), and to provide a research basis for enhancing the benefit of immunotherapy in advanced gastric cancer (AGC). METHODS: MBGC were divided into normal saline group (group NS), apatinib group (group A), PD-1 inhibitors group (group B) and PD-1 inhibitors combined with apatinib group (group C). Tumor inhibition rates were calculated. Cytokine levels and expression of immune cells and molecules were detected, and the pathological manifestations of tumor tissues were observed. RESULTS: Group C had the smallest tumor volume (115.17 ± 16.08 mm3) with a tumor inhibition rate of 89.4% ± 0.69%, significantly increased levels of CD4+T and CD8+T cells in tumor tissues (P < 0.01), the down-regulated proportion of myeloid-derived suppressor cells (MDSCs) (P < 0.01), and levels of PD-1 of CD8+T cells (PD-1+CD8+T) (P < 0.01). There was no difference in the levels of PD-1+CD8+T, CD4+T cells, and MDSCs between groups B and C. Besides, combination therapy increased the levels of interleukin-2 (IL-2), interferon-gamma (IFN-γ), and tumor necrosis factor-ɑ (TNF-ɑ) in tumor tissue and serum. We also found that the anti-angiogenic effect of apatinib increased programmed death ligand-1 (PD-L1) levels, down-regulated vascular endothelial growth factor receptor 2 (VEGFR-2) levels, and induced an increase in the extent of tumor tissue necrosis. CONCLUSION: PD-1 inhibitors in combination with apatinib may help improve treatment outcomes and increase survival benefits in patients with AGC.

The impact of main air pollutants on respiratory emergency department visits and the modification effects of temperature in Beijing, China.

Research indicates that air pollution is a risk factor of an increased occurrence of diseases. However, evidence is limited on the effects of the pollution index on disease and whether temperature modifies the effects. The objectives were (i) to explore the effects of the Air Pollution Index (API) and specific indices for pollutants (PM10, NO2, and SO2) on respiratory emergency department (ED) visits in Beijing and (ii) to investigate whether temperature modified the effects of main air pollutants on respiratory ED visits. A quasi-Poisson generalized additive model was employed to examine the association of API and indices for pollutants with respiratory disease. Bivariate response surface model and stratification model (cold days, moderately cold days, moderately hot days, and hot days) were used to analyze the modification effects of temperature on air pollution and respiratory disease. The results showed that (i) the effects of API on respiratory diseases were similar to the index for PM10 in Beijing. (ii) API and PM10 were associated with increased respiratory ED visits on cold days and moderately cold days. Furthermore, the effects of PM10 on respiratory disease on moderately cold days [Relative risk (RR) = 1.006 per 10 µg/m3, 95% CI 1.002-1.009] were stronger than on cold days (RR = 1.004 per 10 µg/m3, 95% CI 1.000-1.008). (iii) PM10 (API) had a greater impact on children aged 10 to 17 years and females on moderately cold days, while the elderly had an increased risk of respiratory disease to PM10 (RR = 1.008 per 10 µg/m3, 95% CI 1.002-1.013) and API (RR = 1.013 per 10, 95% CI 1.004-1.022) on cold days. In conclusion, temperature can modify the association between API and respiratory morbidity. A stronger correlation existed between PM10 and respiratory diseases on moderately cold days, while the effects of cold days were less than that attributable to moderately cold days.

Prognostic significance and therapeutic potential of the immune checkpoint VISTA in pancreatic cancer.

OBJECTIVE: V-domain Ig suppressor of T cell activation (VISTA) is a novel immune checkpoint protein that belongs to the B7 family. The aim of this study was to investigate the prognostic significance and therapeutic potential of VISTA in patients with pancreatic cancer. METHODS: Using immunohistochemistry (IHC), we examined the expression of VISTA and demonstrated the associations between the VISTA and overall survival in 223 PDAC patients from 2 different unrelated retrospective cohorts. The multiplex immunofluorescence was performed to illuminate the relationship between VISTA expression and tumor-infiltrating immune cell subclusters of PDAC. We also verified the findings in The Cancer Genome Atlas (TCGA) dataset. The anti-tumor effect of anti-VISTA therapy was studied by the mouse model with liver metastases of PDAC. RESULTS: The VISTA protein was highly expressed in 25.6% of tumor cells (TCs), 38.1% of immune cells, and 26.0% of endothelial cells in 223 PDAC tumor tissues. VISTA expression in TCs was significantly associated with prolonged overall survival. Multiplex immunofluorescence analysis revealed that VISTA level was positively correlated with CD68+ macrophages, CD3+ T cells, and CD19+ B cells in PDAC. However, a higher expression level of VISTA was detected in tumor-infiltrating CD68+ macrophages than in CD3+ T and CD19+ B cells. Furthermore, anti-VISTA antibody treatment significantly reduced the number of metastatic nodules in livers of mouse models of PDAC with liver metastases. CONCLUSION: VISTA expressed in TCs is associated with a favorable prognosis in PDAC. Moreover, immunotherapy with anti-VISTA antibodies may potentially be an effective treatment strategy against PDAC.

High-dimensional single-cell analysis delineates radiofrequency ablation induced immune microenvironmental remodeling in pancreatic cancer.

Radiofrequency ablation (RFA) is an effective local therapy approach for treating solitary tumor of many types of malignancy. The impact of RFA on the tumor immune microenvironment on distant tumors after RFA treatment is still unclear. In this study, by using syngeneic tumor models and single-cell RNA and T-cell receptor sequencing, we have investigated the alterations of tumor-infiltrating immune cells in distant non-RFA tumors. Single-cell RNA sequencing identified six distinct lymphoid clusters, five distinct monocyte/macrophage clusters, three dendritic cells clusters, and one cluster of neutrophils. We found that RFA treatment reduced the proportions of immunosuppressive cells including regulatory T cells, tumor-associated macrophages and tumor-associated neutrophils, whereas increased the percentages of functional T cells in distant non-RFA tumors. Moreover, RFA treatment also altered gene expressions in single-cell level in each cell cluster. By using pseudo-time analysis, we have described the biological processes of tumor-infiltrating CD8+ T cells and monocytes/macrophages based on the transcriptional profiles. In addition, the immune checkpoints including PD-1 and LAG3 were upregulated in the T cells in distant non-RFA tumors after RFA treatment. In conclusion, our data indicate that RFA treatment induced remodeling of tumor immune microenvironment in distant non-RFA tumors in pancreatic cancer mouse model and suggest that combining RFA with immune checkpoint inhibitors may be an effective treatment approach.