Radiation could induce DNA damage,cell death,and changes of tumor phenotype and tumor microenvironment leading to the regulation of immune response.Immune checkpoint signaling pathways are involved in the immune tolerance of anti-microorganism responses and thus limit tissue damage.In the anti-tumor immune response,these pathways are associated with anti-functional activation of specific cytotoxic T cells and also enhance the inhibition effect of immune response,which always result in immune escape.Blockade of the immune checkpoint signaling pathways benefits to the anti-tumor inmune responses and could delay tumor progress.As a result,the combination treatment of radiotherapy and immune checkpoint biockade has attracted more attentions in clinical application.This paper reviews the recent research progresses in the radiation effect of immune system,the regulation of immune checkpoints and the combination treatment of radiotherapy and immune checkpoint blockade in tumor therapy,trying to arouse some new clues in cancer therapy.

Activated fibroblasts and M2-polarized macrophages may contribute to the progression of pulmonary fibrosis by forming a positive feedback loop. This study was aimed to investigate whether fibroblasts and macrophages form this loop by secreting SDF-1 and TGF-β and the impacts of neotuberostemonine (NTS) and tuberostemonine (TS). Mice were intratracheally injected with 3 U·kg^-1 bleomycin and orally administered with 30 mg·kg^-1 NTS or TS. Primary pulmonary fibroblasts (PFBs) and MH-S cells (alveolar macrophages) were used in vitro. The animal experiments showed that NTS and TS improved fibrosis related indicators, inhibited fibroblast activation and macrophage M2 polarization, and reduced the levels of TGF-β and SDF-1 in alveolar lavage fluid. Cell experiments showed that TGF-β1 may activated fibroblasts into myofibroblasts secreting SDF-1 by activating the PI3K/AKT/HIF-1α and PI3K/PAK/RAF/ERK/HIF-1α pathways. It was also found for the first time that SDF-1 was able to directly polarize macrophages into M2 phenotype secreting TGF-β through the same pathways as mentioned above. Moreover, the results of the cell coculture confirmed that fibroblasts and macrophages actually developed a feedback loop to promote fibrosis, and the secretion of TGF-β and SDF-1 was crucial for maintaining this loop. NTS and TS may disturb this loop through inhibiting both the PI3K/AKT/HIF-1α and PI3K/PAK/RAF/ERK/HIF-1α pathways to improve pulmonary fibrosis. NTS and TS are stereoisomeric alkaloids with pyrrole[1,2-a]azapine skeleton, and their effect on improving pulmonary fibrosis may be largely attributed to their parent nucleus. Moreover, this study found that inhibition of both the AKT and ERK pathways is essential for maximizing the improvement of pulmonary fibrosis.
Animals ; Mice ; Pulmonary Fibrosis/metabolism* ; Transforming Growth Factor beta/pharmacology* ; Proto-Oncogene Proteins c-akt/metabolism* ; Phosphatidylinositol 3-Kinases/metabolism* ; MAP Kinase Signaling System ; Alkaloids/pharmacology* ; Fibroblasts ; Macrophages/metabolism*

  Objective  Mohr-Tranebjaerg syndrome (MTS) is a rare X-linked neurodegenerative disorder which usually involving hearing impairment, gradual dystonia, and other symptoms. In this study, we perform analyzed the genetic makeup of a family with this rare Mohr-Tranebjaerg syndrome.  Methods  We collected the clinical data of the family, did the whole exome sequencing on the proband Ⅲ6 with a rare mutation, and verified the mutation in another affected family member Ⅲ5 and unaffected members Ⅰ1, Ⅰ2, Ⅱ1, Ⅱ5, Ⅱ7, Ⅱ8, Ⅲ7.  Results  The patients in the family all showed early-onset deafness. More than a couple of affected male members have dystonia with/without mental disorders. Genetic testing results showed the proband Ⅲ6 had a c.133-2delA in TIMM8A (NM_ 004085.3, DDP1), highly likely pathogenic(LP). This variation was detected in affected Ⅲ5 as well as the unaffected females Ⅰ1, Ⅱ5, Ⅱ7.  Conclusions  MTS caused by the rare TIMM8A mutation, the molecular etiology of the family with this rare disease, is highly consistent with the clinical manifestations and segregation. Other than the deafness, other symptoms varied among the affected family members. Genetic diagnosis for such X-linked diseases can also identify female heterozygotes. Genetic and reproduction counseling can help families in the family planning.