Browsing by Author "White, Alisa"

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    In-situ cryo-immune engineering of tumor microenvironment with cold-responsive nanotechnology for cancer immunotherapy
    (Springer Nature, 2023-01-24) Ou, Wenquan; Stewart, Samantha; White, Alisa; Kwizera, Elyahb A.; Xu, Jiangsheng; Fang, Yuanzhang; Shamul, James G.; Xie, Changqing; Nurudeen, Suliat; Tirada, Nikki P.; Lu, Xiongbin; Tkaczuk, Katherine H. R.; He, Xiaoming; Medical and Molecular Genetics, School of Medicine
    Cancer immunotherapy that deploys the host’s immune system to recognize and attack tumors, is a promising strategy for cancer treatment. However, its efficacy is greatly restricted by the immunosuppressive (i.e., immunologically cold) tumor microenvironment (TME). Here, we report an in-situ cryo-immune engineering (ICIE) strategy for turning the TME from immunologically “cold” into “hot”. In particular, after the ICIE treatment, the ratio of the CD8+ cytotoxic T cells to the immunosuppressive regulatory T cells is increased by more than 100 times in not only the primary tumors with cryosurgery but also distant tumors without freezing. This is achieved by combining cryosurgery that causes “frostbite” of tumor with cold-responsive nanoparticles that not only target tumor but also rapidly release both anticancer drug and PD-L1 silencing siRNA specifically into the cytosol upon cryosurgery. This ICIE treatment leads to potent immunogenic cell death, which promotes maturation of dendritic cells and activation of CD8+ cytotoxic T cells as well as memory T cells to kill not only primary but also distant/metastatic breast tumors in female mice (i.e., the abscopal effect). Collectively, ICIE may enable an efficient and durable way to leverage the immune system for combating cancer and its metastasis.
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    Metformin Bicarbonate-Mediated Efficient RNAi for Precise Targeting of TP53 Deficiency in Colon and Rectal Cancers
    (Elsevier, 2022) Xu, Jiangsheng; Liu, Yunhua; Liu, Sheng; Ou, Wenquan; White, Alisa; Stewart, Samantha; Tkaczuk, Katherine H.R.; Ellis, Lee M.; Wan, Jun; Lu, Xiongbin; He, Xiaoming; Medical and Molecular Genetics, School of Medicine
    Colon and rectal cancers are the leading causes of cancer-related deaths in the United States and effective targeted therapies are in need for treating them. Our genomic analyses show hemizygous deletion of TP53, an important tumor suppressor gene, is highly frequent in both cancers, and the 5-year survival of patients with the more prevalent colon cancer is significantly reduced in the patients with the cancer harboring such deletion, although such reduction is not observed for rectal cancer. Unfortunately, direct targeting TP53 has been unsuccessful for cancer therapy. Interestingly, POLR2A, a gene essential for cell survival and proliferation, is almost always deleted together with TP53 in colon and rectal cancers. Therefore, RNA interference (RNAi) with small interfering RNAs (siRNAs) to precisely target/inhibit POLR2A may be an effective strategy for selectively killing cancer cells with TP53 deficiency. However, the difficulty of delivering siRNAs specifically into the cytosol where they perform their function, is a major barrier for siRNA-based therapies. Here, metformin bicarbonate (MetC) is synthesized to develop pH-responsive MetC-nanoparticles with a unique “bomb” for effective cytosolic delivery of POLR2A siRNA, which greatly facilitates its endo/lysosomal escape into the cytosol and augments its therapeutic efficacy of cancer harboring TP53 deficiency. Moreover, the MetC-based nanoparticles without functional siRNA show notable therapeutic effect with no evident toxicity or immunogenicity.