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1.
Cancer Immunol Res ; 11(11): 1553-1567, 2023 11 01.
Article in English | MEDLINE | ID: mdl-37669022

ABSTRACT

The immune checkpoint inhibitor (ICI), anti-programmed death-1 (anti-PD-1), has shown moderate efficacy in some patients with head and neck squamous cell carcinoma (HNSCC). Because of this, it is imperative to establish a mouse tumor model to explore mechanisms of antitumor immunity and to develop novel therapeutic options. Here, we examined the 4-nitroquinoline-1-oxide (4NQO)-induced oral squamous cell carcinoma (OSCC) model for genetic aberrations, transcriptomic profiles, and immune cell composition at different pathologic stages. Genomic exome analysis in OSCC-bearing mice showed conservation of critical mutations found in human HNSCC. Transcriptomic data revealed that a key signature comprised of immune-related genes was increased beginning at the moderate dysplasia stages. We first identified that macrophage composition in primary tumors differed across pathologic stages, leading to an oncogenic evolution through a change in the M1/M2 macrophage ratio during tumorigenesis. We treated the 4NQO-induced OSCC-bearing mice with anti-PD-1 and agonistic anti-CD40, which modulated multiple immune responses. The growth of tumor cells was significantly decreased by agonistic anti-CD40 by promoting an increase in the M1/M2 ratio. By examining cross-species genomic conservation in human and mouse tumors, our study demonstrates the molecular mechanisms underlying the development of OSCC and the regulation of contributing immune-related factors, and aims to facilitate the development of suitable ICI-based treatments for patients with HNSCC.


Subject(s)
Carcinoma, Squamous Cell , Head and Neck Neoplasms , Mouth Neoplasms , Humans , Mice , Animals , Squamous Cell Carcinoma of Head and Neck/genetics , Carcinoma, Squamous Cell/drug therapy , Carcinoma, Squamous Cell/genetics , Carcinoma, Squamous Cell/pathology , Mouth Neoplasms/drug therapy , Mouth Neoplasms/genetics , Transcriptome , Immunotherapy , Disease Models, Animal , Genomics
2.
J Pathol ; 259(4): 428-440, 2023 04.
Article in English | MEDLINE | ID: mdl-36641765

ABSTRACT

Anti-programmed cell death 1 (anti-PD-1) therapy shows definite but modest activity in patients with advanced/metastatic head and neck squamous cell carcinoma (HNSCC). Preliminary evidence suggests that SN-38, an activated form of irinotecan that increases expression of the transcription factor FoxO3a, can suppress programmed cell death ligand-1 (PD-L1) expression in breast and ovarian tumor models. We analyzed the SN-38-mediated activation of natural killer cells in vitro and explored the efficacy of SN-38 in combination with anti-PD-1 for treatment in vivo. In vitro, SN-38 enhanced the expression of FoxO3a and reduced the expression of c-Myc and PD-L1 dose-dependently in tumor cells. Low-dose SN-38 increased interferon-γ secretion by NK cells and promoted NK cell-mediated cytotoxicity in tumor cells. In vivo studies revealed that at non-cytotoxic drug concentrations, SN-38 significantly enhanced anti-PD-1 activity in suppressing murine tumor growth. We found increased NK cell and CD8+ T-cell infiltration in post-treatment tumors. RNA-seq analysis indicated that SN-38 increased the enrichment of immune cells and biological function genes related to the immune responses. SN-38 is a potentially beneficial adjunct to checkpoint inhibitor therapy in HNSCC. Further studies exploring its mechanism of action and possible applications are necessary. © 2023 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.


Subject(s)
B7-H1 Antigen , Head and Neck Neoplasms , Animals , Humans , Mice , Head and Neck Neoplasms/drug therapy , Head and Neck Neoplasms/genetics , Irinotecan/pharmacology , Squamous Cell Carcinoma of Head and Neck/drug therapy , Treatment Outcome
3.
Dev Biol ; 461(1): 96-106, 2020 05 01.
Article in English | MEDLINE | ID: mdl-32007453

ABSTRACT

In Drosophila, the deposition of the germ plasm at the posterior pole of the oocyte is essential for the abdomen and germ cell formation during embryogenesis. To assemble the germ plasm, oskar (osk) mRNA, produced by nurse cells, should be localized and anchored on the posterior cortex of the oocyte. Processing bodies (P-bodies) are cytoplasmic RNA granules responsible for the 5'-3' mRNA degradation. Evidence suggests that the components of P-bodies, such as Drosophila decapping protein 1 and Ge-1, are involved in the posterior localization of osk. However, whether the decapping core enzyme, Drosophila decapping protein 2 (dDcp2), is also involved remains unclear. Herein, we generated a dDcp2 null allele and showed that dDcp2 was required for the posterior localization of germ plasm components including osk. dDcp2 was distributed on the oocyte cortex and was localized posterior to the osk. In the posterior pole of dDcp2 mutant oocytes, osk was mislocalized and colocalized with F-actin detached from the cortex; moreover, considerably fewer F-actin projections were observed. Using the F-actin cosedimentation assay, we proved that dDcp2 interacted with F-actin through its middle region. In conclusion, our findings explored a novel function of dDcp2 in assisting osk localization by modulating the formation of F-actin projections on the posterior cortex.


Subject(s)
Actins/metabolism , Drosophila Proteins/genetics , Drosophila melanogaster/embryology , Embryonic Development/genetics , Animals , Drosophila melanogaster/genetics , Oocytes/cytology , Protein Isoforms/genetics , RNA Stability/physiology , RNA, Messenger/genetics , RNA, Messenger/metabolism
4.
J Immunol ; 178(11): 6984-93, 2007 Jun 01.
Article in English | MEDLINE | ID: mdl-17513748

ABSTRACT

Some polyacetylenes from the plant Bidens pilosa have been reported to treat diabetes. In this study, we report that the cytopiloyne from B. pilosa, which is structurally different from the above-mentioned polyacetylenes and inhibits CD4(+) T cell proliferation, effectively prevents the development of diabetes in nonobese diabetic mice as evidenced by a normal level of blood glucose and insulin and normal pancreatic islet architecture. Cytopiloyne also suppresses the differentiation of type 1 Th cells but promotes that of type 2 Th cells, which is consistent with it enhancing GATA-3 transcription. Also, long-term application of cytopiloyne significantly decreases the level of CD4(+) T cells inside pancreatic lymph nodes and spleens but does not compromise total Ab responses mediated by T cells. Coculture assays imply that this decrease in CD4(+) T cells involves the Fas ligand/Fas pathway. Overall, our results suggest that cytopiloyne prevents type 1 diabetes mainly via T cell regulation.


Subject(s)
Diabetes Mellitus, Type 1/prevention & control , Glucosides/therapeutic use , Polyynes/therapeutic use , Animals , CD4-Positive T-Lymphocytes/cytology , CD4-Positive T-Lymphocytes/drug effects , CD4-Positive T-Lymphocytes/immunology , Cell Differentiation/drug effects , Cell Differentiation/immunology , Cell Line , Cell Proliferation/drug effects , Diabetes Mellitus, Type 1/immunology , Diabetes Mellitus, Type 1/pathology , Female , GATA3 Transcription Factor/biosynthesis , GATA3 Transcription Factor/genetics , Glucosides/administration & dosage , Growth Inhibitors/administration & dosage , Growth Inhibitors/therapeutic use , Lymphocyte Activation/drug effects , Male , Mice , Mice, Inbred NOD , Mice, SCID , Polyynes/administration & dosage , T-Box Domain Proteins/genetics , T-Box Domain Proteins/metabolism , Thymidine/metabolism , Transcription, Genetic/drug effects , Up-Regulation/drug effects , Up-Regulation/immunology
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