Remarkable advances with hepatitis C Virus (HCV) infection therapy have been made over the past 5 years,. At the same time, the peak of morbidity for the HCV epidemic, including outcomes such as cirrhosis and hepatocellular carcinoma (HCC) will not occur until 2030. In fact, HCC is one of the fastest growing cancer related causes of death in the US. Certainly, at some point successful therapy for HCV will reduce the incidence of HCC. Though when this will be realized is unclear, in part due to the fact that the chronic HCV- infected patient population is aging, and older age HCV-infected patients do not appear to derive the same reduction in morbidity after successful HCV therapy as do their younger counterparts. At present, our local VA station (Station 541, Cleveland) follows 3,428 HCV patients, and over the past 3 years has treated over 1,500 of these with IFN-free therapy. Still, we accrue 25-43 new HCC cases/year, running at a steady rate over the past 6 years. Better strategies to more precisely identify those at high risk for HCC, and treat early HCC are much needed to curb this morbidity/mortality. PD1 blockade is an emerging therapy, and while a role for T cells in mediating effects of PD1 blockade have been defined, a role for NK cell activity is less defined. At the same time NK cells are a dominant lymphocyte population within the liver, NK cells are known to contribute to control of HCV infection itself, and NK cells have anti-cancer effector function. We will follow our well characterized HCV infected patient population, taking an NK cell, pathway focused approach to evaluate the anti-tumor host immune response that precedes HCV associated HCC diagnosis, to help identify both predictive markers and new treatment strategies. We hypothesize that NK cells play an integral role in host defense against HCV associated HCC, that selective enhancement of NK cell immune function through modulation of the IFN response or PD1 signaling can be harnessed to improve host anti-HCC immunity with therapeutic potential. Defining NK cell immunity that precedes HCC diagnosis will inform when and how to best inform PD1 or NK targeted clinical trial design, and potentially provide biomarkers of disease risk or onset. We will investigate this hypothesis with the following aims:
Aim 1 : Determine the role of PD1 on NK cell expansion and anti-HCC activity.
Aim 2 : Determine the effect of selective targeting the Long Non-Coding RNA (lncRNA) NRIR (negative regulator of interferon response) in enhancing IFN-dependent anti-HCC activity.
Aim 3 : Define NK cell activation state, function, PD1 pathway engagement and IFN regulatory pathway engagement prior to diagnosis of HCC.
Infection with HCV is particularly prevalent in the veteran population. Roughly 80% of veterans are at sufficient risk as to qualify for screening, and approximately 10% are infected. Infection with HCV constitutes the most common cause of chronic hepatitis in the United States. Many infected patients develop cirrhosis, end stage liver disease, and liver cancer. Liver cancer, and geriatric age are developing issues expected to peak in 2030, though screening and treatment of liver cancer is only modestly effective. Because of these issues, and because Natural Killer (NK) cells are capable of controlling cancer, investigation of the role of NK cells in control of HCV associated hepatocellular carcinoma is needed to guide new screening, monitoring, and treatment strategies.
|Judge, Chelsey J; Kostadinova, Lenche; Sherman, Kenneth E et al. (2017) CD56bright NK IL-7R? expression negatively associates with HCV level, and IL-7-induced NK function is impaired during HCV and HIV infections. J Leukoc Biol 102:171-184|
|Judge, Chelsey J; Sandberg, Johan K; Funderburg, Nicholas T et al. (2016) Brief Report: CD14brightCD16- monocytes and sCD14 level negatively associate with CD4-memory T-cell frequency and predict HCV-decline on therapy. J Acquir Immune Defic Syndr 73:258-262|
|Reyes-Avilés, Elane; Kostadinova, Lenche; Rusterholtz, Anne et al. (2015) Presence of Rheumatoid Factor during Chronic HCV Infection Is Associated with Expansion of Mature Activated Memory B-Cells that Are Hypo-Responsive to B-Cell Receptor Stimulation and Persist during the Early Stage of IFN Free Therapy. PLoS One 10:e0144629|
|Judge, Chelsey J; Reyes-Aviles, Elane; Conry, Sara J et al. (2015) HBD-3 induces NK cell activation, IFN-? secretion and mDC dependent cytolytic function. Cell Immunol 297:61-8|
|Kambara, Hiroto; Niazi, Farshad; Kostadinova, Lenche et al. (2014) Negative regulation of the interferon response by an interferon-induced long non-coding RNA. Nucleic Acids Res 42:10668-80|
|Kambara, Hiroto; Gunawardane, Lalith; Zebrowski, Elizabeth et al. (2014) Regulation of Interferon-Stimulated Gene BST2 by a lncRNA Transcribed from a Shared Bidirectional Promoter. Front Immunol 5:676|
|Meng, Qinglai; Rani, M R Sandhya; Sugalski, Julia M et al. (2014) Natural cytotoxicity receptor-dependent natural killer cytolytic activity directed at hepatitis C Virus (HCV) is associated with liver inflammation, African American race, IL28B genotype, and response to pegylated interferon/ribavirin therapy in chronic H J Infect Dis 209:1591-601|
|Leeansyah, Edwin; Malone, David F G; Anthony, Donald D et al. (2013) Soluble biomarkers of HIV transmission, disease progression and comorbidities. Curr Opin HIV AIDS 8:117-24|