Some chemotherapeutic drugs for cancers trigger reactivation because of cellular stress induced by the drugs. Upon viral reactivation, neo-antigens expressed by tumors become new targets for cytotoxic cells. These neo- antigens include virus lytic antigens, pathogen-associated molecular patterns and surrogate tumor-associated molecules expressed upon viral reactivation. Viral reactivation in tumors also induces tumor cell death and releases tumor-associated immunogenic antigens into the tumor micro-environment or circulation. The latter may boost anti-tumor immune response systemically. Finally, exosomes produced by tumors into circulation, which potentially carry virus genomes and antigens, can be another form of tumor associated immune triggers. Thus, viral reactivation may, in fact, help revive a patients' immune cytotoxicity if we can only control and limit the level and location of viral reactivation. Our in vitro preliminary data suggests that this scenario is achievable in KSHV-positive peritoneal effusion lymphoma (PEL) by the BTZ and OTX015 combination therapy. That is, the treatment of KSHV-positive PELs with BTZ and OTX015 induced reactivation of KSHV and expression of lytic antigens while blocking terminal viral particle formation, resulting in PEL cell death with limited shedding of mature viral particles. In addition, OTX015 showed strong suppression of inflammatory cytokine production by PEL. In this supplement project, the candidate, Dr. Shimoda will introduce a humanized mouse model to test the hypothesis that BTZ/OTX015 therapy creates immunogenic tumor micro-environment in a humanized mouse model of PEL.
Specific Aims are:
Aim 1 : To evaluate immune phenotype in a humanized mouse model of PEL under BTZ/OTX015 therapy. We will test the hypothesis that KSHV reactivation by BTZ/OTX015 in HLA-A0201-restricted BC-3 tumors results in increased tumor-infiltrating immune cells with overall enhanced cytotoxicity. Immune cell phenotype and the frequency of cytotoxic CD107a+ and IFNg+ cells in spleen and tumors will be evaluated by flow cytometry. Our goal is to establish that the drug combination has overall beneficial effect on anti-tumor immune response.
Aim 2 : To conduct single cell transcriptome analysis of the tumor micro-environment during BTZ/OTX015 therapy. We will test the hypothesis that transcriptional changes induced in a tumor micro- environment by drugs in huPBL-NSG PEL mice can be identified by single cell RNA sequencing technology. We will evaluate the drug effects on PEL tumors as well as tumor infiltrating immune cells at single cell level. Our goal is to identify the drug and cell-specific unique transcriptome changes in tumor and immune cell subsets.
Kaposi's sarcoma-associated herpesvirus (KSHV) causes Kaposi's sarcoma and B cell lymphomas, and currently there are not any good options available for the treatment of these diseases. Nano-medicine demonstrates great promise in improving drug efficacy by increasing local concentration and lowering the administered dosage. In this project, we will investigate the effects of nano-medicine on immune cells as a supplement to the parent R01, the main focus of which is to establish a Nanoparticle mediated drug delivery methods for oncogenic herpesvirus mediated malignancies and evaluate their efficacies.
| Yuan, Ye; He, Yixuan; Bo, Ruonan et al. (2018) A facile approach to fabricate self-assembled magnetic nanotheranostics for drug delivery and imaging. Nanoscale 10:21634-21639 |
