ABSTRACT
Tumor migration/metastasis and immunosuppression are major obstacles in effective cancer therapy. Incidentally, these 2 hurdles usually coexist inside tumors, therefore making therapy significantly more complicated, as both oncogenic mechanisms must be addressed for successful therapeutic intervention. Our recent report highlights that the tumor expression of a TNF family member, CD70, is correlated with poor survival for primary gliomas. In this study, we investigated how CD70 expression by GBM affects the characteristics of tumor cells and the tumor microenvironment. We found that the ablation of CD70 in primary GBM decreased CD44 and SOX2 gene expression, and inhibited tumor migration, growth and the ability to attract monocyte-derived M2 macrophages in vitro. In the tumor microenvironment, CD70 was associated with immune cell infiltrates, such as T cells; myeloid-derived suppressor cells; and monocytes/macrophages based on the RNA-sequencing profile. The CD163+ macrophages were far more abundant than T cells were. This overwhelming level of macrophages was identified only in GBM and not in low-grade gliomas and normal brain specimens, implying their tumor association. CD70 was detected only on tumor cells, not on macrophages, and was highly correlated with CD163 gene expression in primary GBM. Additionally, the co-expression of the CD70 and CD163 genes was found to correlate with decreased survival for patients with primary GBM. Together, these data suggest that CD70 expression is involved in promoting tumor aggressiveness and immunosuppression via tumor-associated macrophage recruitment/activation. Our current efforts to target this molecule using chimeric antigen receptor T cells hold great potential for treating patients with GBM.
Subject(s)
Brain Neoplasms/metabolism , Brain Neoplasms/pathology , CD27 Ligand/metabolism , Glioblastoma/metabolism , Glioblastoma/secondary , Immune Tolerance , Antigens, CD/analysis , Antigens, CD/genetics , Antigens, CD/metabolism , Antigens, Differentiation, Myelomonocytic/analysis , Antigens, Differentiation, Myelomonocytic/genetics , Antigens, Differentiation, Myelomonocytic/metabolism , Brain/cytology , Brain Neoplasms/immunology , CD27 Ligand/analysis , CD27 Ligand/genetics , Cell Line, Tumor , Cell Migration Assays, Macrophage/methods , Cell Movement , Gene Expression Regulation, Neoplastic , Glioblastoma/immunology , Glioblastoma/mortality , Humans , Hyaluronan Receptors/genetics , Hyaluronan Receptors/metabolism , Immunity, Cellular , Macrophages/chemistry , Macrophages/cytology , Macrophages/immunology , Neoplasm Metastasis , Receptors, Cell Surface/analysis , Receptors, Cell Surface/genetics , Receptors, Cell Surface/metabolism , SOXB1 Transcription Factors/genetics , SOXB1 Transcription Factors/metabolism , T-Lymphocytes/cytology , T-Lymphocytes/immunology , Tumor Microenvironment/immunologyABSTRACT
OBJECTIVE: We examined whether the modulatory effect of pregnancy on multiple sclerosis (MS) is associated with changes in the apoptotic molecules in sera. SUBJECTS AND METHODS: The serum levels of tumor necrosis factor-related apoptosis-inducing ligand (sTRAIL), sFas, Fas ligand (sFasL) and macrophage migration inhibitory factor were analyzed from 19 MS patients and 14 controls during late pregnancy and post-partum. The obtained results were related to disease activity and the progression of MS. RESULTS: Disease activity decreased during pregnancy. The levels of sTRAIL and sFasL increased from late pregnancy to post-partum situation in both MS patients and controls, but in MS patients the changes in the levels of sTRAIL from late pregnancy to post-partum were smaller than in controls. CONCLUSIONS: Post-partum upregulation of TRAIL and FasL seems to be caused by physiologic reactivation of the mother's immune system after pregnancy. An increased risk of relapses in MS post-partum may be associated with changes in the immunomodulatory potential of these apoptotic molecules.
