ABSTRACT
PURPOSE: Ablative hypofractionated radiation therapy (AHFRT) presents a therapeutic advantage compared with conventional fractionated radiation therapy (CFRT) for primary and oligometastatic cancers. However, the underlying mechanisms remain largely unknown. In the present study, we compared the immune alterations in response to AHFRT versus CFRT and examined the significance of immune regulations contributing to the efficacy of AHFRT. METHODS AND MATERIALS: We established subcutaneous tumors using syngeneic lung cancer and melanoma cells in both immunocompetent and immunocompromised mice and treated them with AHFRT and CFRT under the same biologically equivalent dose. RESULTS: Compared with CFRT, AHFRT significantly inhibited tumor growth in immunocompetent, but not immunocompromised, mice. On the cellular level, AHFRT reduced the recruitment of myeloid-derived suppressor cells (MDSCs) into tumors and decreased the expression of programmed death-ligand 1 (PD-L1) on those cells, which unlashed the cytotoxicity of CD8+ T cells. Through the downregulation of vascular endothelial growth factor (VEGF), AHFRT inhibited VEGF/VEGF receptor signaling, which was essential for MDSC recruitment. When combined with anti-PD-L1 antibody, AHFRT presented with greater efficacy in controlling tumor growth and improving mouse survival. By altering immune regulation, AHFRT, but not CFRT, significantly delayed the growth of secondary tumors implanted outside the irradiation field. CONCLUSIONS: Targeting MDSC recruitment and enhancing antitumor immunity are crucial for the therapeutic efficacy of AHFRT. When combined with anti-PD-L1 immunotherapy, AHFRT was more potent for cancer treatment.
Subject(s)
B7-H1 Antigen/therapeutic use , Carcinoma, Lewis Lung/radiotherapy , Immunotherapy, Adoptive/methods , Melanoma, Experimental/radiotherapy , Myeloid-Derived Suppressor Cells/radiation effects , Programmed Cell Death 1 Receptor/metabolism , Radiation Dose Hypofractionation , Animals , CD8-Positive T-Lymphocytes/radiation effects , Carcinoma, Lewis Lung/immunology , Carcinoma, Lewis Lung/metabolism , Carcinoma, Lewis Lung/pathology , Combined Modality Therapy/methods , Dose Fractionation, Radiation , Flow Cytometry , Immunocompetence , Immunocompromised Host , Lymphocytes, Tumor-Infiltrating/radiation effects , Melanoma, Experimental/immunology , Melanoma, Experimental/metabolism , Melanoma, Experimental/pathology , Mice , Mice, Inbred BALB C , Mice, Inbred C57BL , Mice, Nude , Myeloid-Derived Suppressor Cells/cytology , Programmed Cell Death 1 Receptor/antagonists & inhibitors , Programmed Cell Death 1 Receptor/immunology , Random Allocation , Receptors, Vascular Endothelial Growth Factor/antagonists & inhibitors , Receptors, Vascular Endothelial Growth Factor/metabolism , Receptors, Vascular Endothelial Growth Factor/radiation effects , Relative Biological Effectiveness , Tumor Burden/radiation effects , Vascular Endothelial Growth Factor A/antagonists & inhibitors , Vascular Endothelial Growth Factor A/metabolism , Vascular Endothelial Growth Factor A/radiation effectsABSTRACT
In the present study, the synthesis of hapten for the organophosphorus (OP) pesticide paraoxon-methyl was developed, with a spacer arm (aminocarboxylic acid) attached at the aromatic ring. It was conjugated to bovine serum albumin (BSA) for use as an immunogen and to ovalbumin (OVA) for coating antigen for ELISA testing. Rabbits were immunized with the immunogen and two polyclonal antisera were produced and screened against the coating antigen using competitive indirect enzyme-linked immunosorbent assay (ELISA). For application to textile samples, the influence of several factors such as organic solvent, ionic strength, and pH on the ELISA results were studied. Under optimized conditions, the quantitative working range was 0.012-1.158 microg/mL with a limit of detection (LOD) of 0.005 microg/mL and the IC(50) was 0.115 microg/mL.There was negligible cross reactivity (CR) with other OP pesticides. The recoveries obtained by standard paraoxon-methyl addition to the different textile samples such as cotton, wool and muslin delaine were all from 86.0% to 108.0%. Therefore, the optimized ELISA may become a new convenient and economical analytical tool for monitoring paraoxon-methyl residues in textile samples.
