Targeting Tumor-Resident Myeloid Cells Via BTK Inhibition to Enhance Oncolytic Viroimmunotherapy
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Date
2021-05
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The Ohio State University
Abstract
Pediatric sarcomas are highly aggressive cancers that metastasize quickly and can return after treatment. Despite the use of harsh treatments, survival rates for older children and those with metastatic disease remain low. Oncolytic virotherapy is a promising treatment option for pediatric sarcomas that aims to destroy cancer cells and induce antitumor immunity using live, attenuated viruses such as herpes simplex-1 viruses (oHSV). Virotherapy, however, also stimulates the recruitment of tumor-associated immunosuppressive cells, like myeloid-derived suppressor cells (MDSC) and tumor-associated macrophages (TAM), to the tumor microenvironment. Such immunosuppressive cells limit the ability of the virus to replicate and spread. We hypothesize that this recruitment results in reduced therapeutic efficacy. Previous studies show that trabectedin, a chemotherapeutic, in combination with oHSV treatment enhances the efficacy of virotherapy in A673 Ewing sarcoma models. This is likely due to trabectedin's ability to suppress TAM and MDSC recruitment to the tumor microenvironment. We termed this combination "myelolytic-virotherapy." Though trabectedin was able to enhance oHSV virotherapy through the reduction of immunosuppressive cell recruitment, this mechanism is not well understood. Thus, there is a need to understand if solely targeting tumor-resident MDSC enhances virotherapy. By determining if targeting MDSC improves the efficacy of oncolytic virotherapy, we can develop novel myelolytic-virotherapies that have increased therapeutic efficacy in multiple tumor models. This could have great potential for pediatric cancer patients. Previous studies have also shown that the efficacy of oHSV virotherapy may be dependent on virus-induced antitumor T cell responses. Treatment with oHSV enhanced overall survival and induced T cell recruitment to the tumor microenvironment in M3-9-M rhabdomyosarcoma models. Therefore, there is an additional need to investigate whether antitumor T cell responses are necessary to enhance the efficacy of oncolytic virotherapy, or if solely suppressing MDSC is enough. A study conducted by Dr. William Carson found that ibrutinib, an irreversible Bruton's tyrosine kinase (BTK) inhibitor, selectively reduces MDSC recruitment to tumors and limits their ability to suppress T cell proliferation. Ibrutinib also improved the efficacy of immune based cancer therapies. We hypothesize that ibrutinib enhances oncolytic virotherapy in Ewing sarcoma and rhabdomyosarcoma models by inhibiting tumor-associated MDSC recruitment and enhancing viral replication. In this study, we performed cellular infiltrate and viral replication studies in A673 Ewing sarcoma models to evaluate the effect of ibrutinib on MDSC recruitment and oHSV replication in vivo. We also performed survival studies in A673 and M3-9-M tumor-bearing mice to determine the effect of ibrutinib on tumor growth and survival. The results indicate that while ibrutinib does reduce MDSC recruitment to the microenvironment, it does not enhance oHSV replication or improve the efficacy of oHSV virotherapy.
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Keywords
Virotherapy, Pediatric cancer, Myeloid cell, Immunology, Ewing sarcoma, Rhabdomyosarcoma