Biology subjects

Serbinowski, E.

Publications and source records attributed to Serbinowski, E..

3 recordsLinked to original sources

bioRxiv2019

Malignant liver cancers have distinct myeloid-derived suppressor cell signatures

Myeloid-derived suppressor cells (MDSCs) are immunosuppressive cells that are increased in patients with numerous malignancies including viral-derived hepatocellular carcinoma (HCC). Here, we report an elevation of MDSC in other hepatobiliary malignancies including non-viral HCC, neuroendocrine tumors (NET), colorectal carcinoma with liver metastases (CRLM), but not cholangiocarcinoma (CCA). Investigation of myeloid cell infiltration in HCC, NET and intrahepatic CCA tumors further established that the frequency of antigen-presenting cells was limited compared to benign lesions suggesting that primary and metastatic hepatobiliary cancers have distinct peripheral and tumoral myeloid signatures. Bioinformatics analysis of the Cancer Genome Atlas demonstrated that a high MDSC score in HCC patients predicted poor disease outcome. Mechanistic studies indicated that the oncometabolite D-2-hydroxyglutarate resulting from isocitrate dehydrogenase 1 mutation could be a limiting factor of MDSC accumulation in CCA patients. Given our observation that MDSCs are increased in non-CCA malignant liver cancers, they may comprise suitable targets for effective immunotherapy approaches.

pathology↗

bioRxiv2018

Global immune fingerprinting in glioblastoma reveals immune-suppression signatures associated with prognosis

Abstract/SummaryGlioblastoma (GBM) remains uniformly lethal, and, despite a large accumulation of immune cells in the microenvironment, there is limited anti-tumor immune response, even with newly developed immune checkpoint therapies. To overcome these challenges and enhance the efficacy of immunotherapies, a comprehensive understanding of the immune system in GBM and changes during disease progression is required. Here, we integrated multi-parameter flow cytometry and mass cytometry time of flight (CyTOF) analysis of patient blood to determine changes in the immune system among tumor types and over disease progression. Utilizing multi-parameter flow cytometry analysis in a cohort of over 250 patients with brain tumors ranging from benign to malignant primary and metastatic, we found that GBM patients had a significant elevation in myeloid-derived suppressor cells (MDSCs) in blood, but not immunosuppressive T regulatory cells. We validated these findings in GBM patient tissue and found that increased numbers of MDSCs in recurrent GBM portended poor prognosis. CyTOF analysis of peripheral blood from a cohort of newly diagnosed GBM patients revealed that reduction in MDSC frequency over time is accompanied by a concomitant increase in dendritic cells and natural killer cells. This reduced MDSC profile was present in GBM patients with extended survival and was similar to that of low-grade glioma (LGG) patients. Our findings provide a rationale for developing strategies to target MDSCs, which are elevated in GBM patients and predict poor prognosis, either by directly targeting or by shifting the immune profile to induce differentiation toward the immune profile of LGGs.

cancer biology↗

bioRxiv2018

Development of a Cx46 targeting strategy for cancer stem cells

Gap junction-mediated cell-cell communication enables tumor cells to synchronize the execution of complex processes. Despite the connexin family of gap junction proteins being considered tumor suppressors, we previously found that glioblastoma cancer stem cells (CSCs) express higher levels of Cx46 compared to non-stem tumor cells, and this was necessary and sufficient for CSC maintenance. To develop a Cx46 targeting strategy, we utilized point mutants to disrupt specific functions of Cx46 and found that gap junction coupling was the critical function of Cx46 for CSCs. Based on this finding, we screened a clinically relevant library of small molecules and identified clofazimine as an inhibitor of Cx46-specific cell-cell communication. Clofazimine attenuated proliferation, self-renewal, and tumor growth and synergized with temozolomide to induce apoptosis. These data suggest that combining clofazimine with standard-of-care therapies may target glioblastoma CSCs. Furthermore, these results demonstrate the importance of targeting cell-cell communication as an anti-cancer therapy.

cancer biology↗