Targeting NF-κB Pathway Through IRAK4 Renders Immune Checkpoint Blockade Effective in Pancreatic Cancer
Dr. Vikas Somani | Post-Doctoral Research Associate at Washington University in St. Louis, Department of Internal Medicine - Division of Oncology
Currently Vikas is working in the area of pancreatic cancer immunotherapy where he is majorly engaged in understanding the precise mechanisms of immune responsive Pancreatic Tumor lacking IRAK4 precise mechanisms of immune responsive Pancreatic Tumor lacking IRAK4.
Authors: Daoxiang Zhang1, Vikas Somani1, Paarth B. Dodhiawala1, Patrick M. Grierson1, Lin Li1, Kuljeet Seehra1, Xiuting Liu1, Brett L. Knolhoff1, Mariana B. Ruzinova2, David G. DeNardo1, Kian-Huat Lim1,*
1Division of Oncology, Department of Internal Medicine, Barnes-Jewish Hospital and The Alvin J. Siteman Comprehensive Cancer Center, Washington University School of Medicine, St. Louis, MO 63110
2Department of Pathology and Immunology, Barnes-Jewish Hospital and The Alvin J. Siteman Comprehensive Cancer Center, Washington University School of Medicine, St. Louis, MO 63110
Effective immunotherapy in pancreatic ductal adenocarcinoma (PDAC) is impeded by multiple barriers in the tumor microenvironment. These include the dense extracellular matrix (ECM), excessive inhibitory myeloid cells, cytokines and chemokines which collectively incapacitate anti-tumour T cells. Constitutive activation the NF-ΚB pathway is a mechanism that drives intrinsic survival of PDAC cells and stromal fibrosis, but its impact on anti-tumour immunity has not been investigated. Using The Cancer Genome Atlas database, we found that expression of RELA, a canonical NF-ΚB factor, in PDAC samples is associated with activated stroma and lower cytotoxic T cell signatures. In a PDAC tissue microarray, the staining intensity of phospho-IRAK4, the innate immune kinase that drives NF-ΚB signaling, negatively correlates with T cell abundance. Based on these findings, we investigated the immunological impact role of IRAK4 in PDAC. Transcriptomic analysis showed that ablation of IRAK4 in PDAC cells downregulates NF-ΚB and inflammatory signatures, and markedly decreases transcription of hyaluronan synthase 2 (HAS2). Accordingly, pharmacologic inhibition of IRAK4 significantly decreased intratumoral hyaluronan, as well as collagen, in autochthonous PDAC mice and potentiated standard chemotherapy. Furthermore, IRAK4 inhibition also significantly reduced production of several suppressive chemokines and checkpoint ligands PD-L1 and Nectin2, leading to revitalization of infiltrative CD4+ and CD8+ T cells. These effects were partly mediated through reduction of intratumoural hyaluronan, which we recapitulated with HAS inhibitor, 4-MU. Accordingly, combined IRAK4 inhibitors with immune checkpoint blockade (ICB) especially anti-CTLA4, were highly efficacious in abrogating tumour growth in autochthonous PDAC mice and doubling their survival. In summary, we showed that targeting the NF-ΚB pathway through IRAK4 renders ICB effective via multiple mechanisms and should be tested in clinical trials for PDAC patients.
Discovering Data Driven Biomarkers for Uveal Melanoma
Deepak Kempuraj, University of Missouri, Department of Neurology
Deepak’s current research affiliation is with the Veteran’s Hospital at the University of Missouri in the Department of Neurology. During this time with the University of Missouri’s Department of Neurology, Deepak has gained his first experience with the Publication of a Research Paper: Neuroprotective Effects of Flavone Luteolin in Neuroinflammation and Neurotrauma. In October of 2020, Deepak participated in his first research conference, the University of California San Diego (UCSD) Institute for Genomic Medicine Symposium, by submitting and presenting a poster presentation: Discovering Potential Biomarkers for Uveal Melanoma Targeted Therapy. He continues his conference experience by submitting and presenting this poster at the 2020 Annual Life Science Exhibits Research Supplier Product Show held for the University of Missouri on November 12, 2020: Discovering Data Driven Biomarkers for Uveal Melanoma.
Authors: Deepak Kempuraj1 and Murugesan Raju2
1David H. Hickman High School, Columbia Public School, Columbia, MO 65203.
2MU Institute for Data Science and Informatics, University of Missouri, Columbia MO 65211.
Genotype-directed targeted therapy has been widely accepted in the health care regimes for personalized medicine. The identification of genetic alterations in genes is a powerful tool to achieve this goal. The protein-coding region of the human genome is called the exome. Sequencing the exome is an efficient way to identify coding variants across a genome in diseases versus healthy subject samples. Though the exome represents less than 2% of the genome, it contains ~85% of known disease-related variants, making the whole-exome sequence a critical tool to discover biomarkers for the pathological condition. Uveal (ocular) melanoma is a common intraocular tumor and the exact cause is unknown. In this study, we used publicly available exome databases such as the cancer genome atlas (TCGA) to investigate biomarkers for Uveal melanoma. We retrieved about 80 uveal melanoma tumor cases of their genomic and RNA seq data. We analyzed the data using TCGA workflow-Bioconductor in the R package. Several novel biomarkers/SNP were identified and found to be associated with Uveal melanoma, including SF3B1, BAP1, EIF1AX etc. The BAP1 mutated gene has been known to be associated with a unique global DNA methylation profile. This biomarker may be a potential gene-based targeted therapy for Uveal melanoma.