IU Indianapolis ScholarWorks :: Browsing by Author "Fang, Yuanzhang"

Browsing by Author "Fang, Yuanzhang"

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Atractylenolide I enhances responsiveness to immune checkpoint blockade therapy by activating tumor antigen presentation
(The American Society for Clinical Investigation, 2021-05-17) Xu, Hanchen; Van der Jeught, Kevin; Zhou, Zhuolong; Zhang, Lu; Yu, Tao; Sun, Yifan; Li, Yujing; Wan, Changlin; So, Ka Man; Liu, Degang; Frieden, Michael; Fang, Yuanzhang; Mosley, Amber L.; He, Xiaoming; Zhang, Xinna; Sandusky, George E.; Liu, Yunlong; Meroueh, Samy O.; Zhang, Chi; Wijeratne, Aruna B.; Huang, Cheng; Ji, Guang; Lu, Xiongbin; Medical and Molecular Genetics, School of Medicine
One of the primary mechanisms of tumor cell immune evasion is the loss of antigenicity, which arises due to lack of immunogenic tumor antigens as well as dysregulation of the antigen processing machinery. In a screen for small-molecule compounds from herbal medicine that potentiate T cell–mediated cytotoxicity, we identified atractylenolide I (ATT-I), which substantially promotes tumor antigen presentation of both human and mouse colorectal cancer (CRC) cells and thereby enhances the cytotoxic response of CD8+ T cells. Cellular thermal shift assay (CETSA) with multiplexed quantitative mass spectrometry identified the proteasome 26S subunit non–ATPase 4 (PSMD4), an essential component of the immunoproteasome complex, as a primary target protein of ATT-I. Binding of ATT-I with PSMD4 augments the antigen-processing activity of immunoproteasome, leading to enhanced MHC-I–mediated antigen presentation on cancer cells. In syngeneic mouse CRC models and human patient–derived CRC organoid models, ATT-I treatment promotes the cytotoxicity of CD8+ T cells and thus profoundly enhances the efficacy of immune checkpoint blockade therapy. Collectively, we show here that targeting the function of immunoproteasome with ATT-I promotes tumor antigen presentation and empowers T cell cytotoxicity, thus elevating the tumor response to immunotherapy.
Heterozygous deletion of chromosome 17p renders prostate cancer vulnerable to inhibition of RNA polymerase II
(Springer Nature, 2018-10-22) Li, Yujing; Liu, Yunhua; Xu, Hanchen; Jiang, Guanglong; Van der Jeught, Kevin; Fang, Yuanzhang; Zhou, Zhuolong; Zhang, Lu; Frieden, Michael; Wang, Lifei; Luo, Zhenhua; Radovich, Milan; Schneider, Bryan P.; Deng, Yibin; Liu, Yunlong; Huang, Kun; He, Bin; Wang, Jin; He, Xiaoming; Zhang, Xinna; Ji, Guang; Lu, Xiongbin; Medical and Molecular Genetics, School of Medicine
Heterozygous deletion of chromosome 17p (17p) is one of the most frequent genomic events in human cancers. Beyond the tumor suppressor TP53, the POLR2A gene encoding the catalytic subunit of RNA polymerase II (RNAP2) is also included in a ~20-megabase deletion region of 17p in 63% of metastatic castration-resistant prostate cancer (CRPC). Using a focused CRISPR-Cas9 screen, we discovered that heterozygous loss of 17p confers a selective dependence of CRPC cells on the ubiquitin E3 ligase Ring-Box 1 (RBX1). RBX1 activates POLR2A by the K63-linked ubiquitination and thus elevates the RNAP2-mediated mRNA synthesis. Combined inhibition of RNAP2 and RBX1 profoundly suppress the growth of CRPC in a synergistic manner, which potentiates the therapeutic effectivity of the RNAP2 inhibitor, α-amanitin-based antibody drug conjugate (ADC). Given the limited therapeutic options for CRPC, our findings identify RBX1 as a potentially therapeutic target for treating human CRPC harboring heterozygous deletion of 17p.
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.
MAL2 drives immune evasion in breast cancer by suppressing tumor antigen presentation
(The American Society for Clinical Investigation, 2021-01-07) Fang, Yuanzhang; Wang, Lifei; Wan, Changlin; Sun, Yifan; Van der Jeught, Kevin; Zhou, Zhuolong; Dong, Tianhan; So, Ka Man; Yu, Tao; Li, Yujing; Eyvani, Haniyeh; Colter, Austyn B.; Dong, Edward; Cao, Sha; Wang, Jin; Schneider, Bryan P.; Sandusky, George E.; Liu, Yunlong; Zhang, Chi; Lu, Xiongbin; Zhang, Xinna; Medical and Molecular Genetics, School of Medicine
Immune evasion is a pivotal event in tumor progression. To eliminate human cancer cells, current immune checkpoint therapy is set to boost CD8+ T cell-mediated cytotoxicity. However, this action is eventually dependent on the efficient recognition of tumor-specific antigens via T cell receptors. One primary mechanism by which tumor cells evade immune surveillance is to downregulate their antigen presentation. Little progress has been made toward harnessing potential therapeutic targets for enhancing antigen presentation on the tumor cell. Here, we identified MAL2 as a key player that determines the turnover of the antigen-loaded MHC-I complex and reduces the antigen presentation on tumor cells. MAL2 promotes the endocytosis of tumor antigens via direct interaction with the MHC-I complex and endosome-associated RAB proteins. In preclinical models, depletion of MAL2 in breast tumor cells profoundly enhanced the cytotoxicity of tumor-infiltrating CD8+ T cells and suppressed breast tumor growth, suggesting that MAL2 is a potential therapeutic target for breast cancer immunotherapy.
Metabolic interventions: A new insight into the cancer immunotherapy
(Elsevier, 2021) Yu, Tao; Dong, Tianhan; Eyvani, Haniyeh; Fang, Yuanzhang; Wang, Xiyu; Zhang, Xinna; Lu, Xiongbin; Medical and Molecular Genetics, School of Medicine
Metabolic reprogramming confers cancer cells plasticity and viability under harsh conditions. Such active alterations lead to cell metabolic dependency, which can be exploited as an attractive target in development of effective antitumor therapies. Similar to cancer cells, activated T cells also execute global metabolic reprogramming for their proliferation and effector functions when recruited to the tumor microenvironment (TME). However, the high metabolic activity of rapidly proliferating cancer cells can compete for nutrients with immune cells in the TME, and consequently, suppressing their anti-tumor functions. Thus, therapeutic strategies could aim to restore T cell metabolism and anti-tumor responses in the TME by targeting the metabolic dependence of cancer cells. In this review, we highlight current research progress on metabolic reprogramming and the interplay between cancer cells and immune cells. We also discuss potential therapeutic intervention strategies for targeting metabolic pathways to improve cancer immunotherapy efficacy.
An organoid-based screen for epigenetic inhibitors that stimulate antigen presentation and potentiate T-cell-mediated cytotoxicity
(Springer Nature, 2021) Zhou, Zhuolong; Van der Jeught, Kevin; Fang, Yuanzhang; Yu, Tao; Li, Yujing; Ao, Zheng; Liu, Sheng; Zhang, Lu; Yang, Yang; Eyvani, Haniyeh; Cox, Mary L.; Wang, Xiyu; He, Xiaoming; Ji, Guang; Schneider, Bryan P.; Guo, Feng; Wan, Jun; Zhang, Xinna; Lu, Xiongbin; Medical and Molecular Genetics, School of Medicine
In breast cancer, genetic heterogeneity, the lack of actionable targets and immune evasion all contribute to the limited clinical response rates to immune checkpoint blockade therapy. Here, we report a high-throughput screen based on the functional interaction of mouse- or patient-derived breast tumour organoids and tumour-specific cytotoxic T cells for the identification of epigenetic inhibitors that promote antigen presentation and potentiate T-cell-mediated cytotoxicity. We show that the epigenetic inhibitors GSK-LSD1, CUDC-101 and BML-210, identified by the screen, display antitumour activities in orthotopic mammary tumours in mice, that they upregulate antigen presentation mediated by the major histocompatibility complex class I on breast tumour cells and that treatment with BML-210 substantially sensitized breast tumours to the inhibitor of the checkpoint programmed death-1. Standardized measurements of tumour-cell killing activity facilitated by tumour-organoid-T-cell screens may help with the identification of candidate immunotherapeutics for a range of cancers.
Somatic mutation of the cohesin complex subunit confers therapeutic vulnerabilities in cancer
(American Society for Clinical Investigation, 2018-07-02) Liu, Yunhua; Xu, Hanchen; Van der Jeught, Kevin; Li, Yujing; Liu, Sheng; Zhang, Lu; Fang, Yuanzhang; Zhang, Xinna; Radovich, Milan; Schneider, Bryan P.; He, Xiaoming; Huang, Cheng; Zhang, Chi; Wan, Jun; Ji, Guang; Lu, Xiongbin; Surgery, School of Medicine
A synthetic lethality-based strategy has been developed to identify therapeutic targets in cancer harboring tumor-suppressor gene mutations, as exemplified by the effectiveness of poly ADP-ribose polymerase (PARP) inhibitors in BRCA1/2-mutated tumors. However, many synthetic lethal interactors are less reliable due to the fact that such genes usually do not perform fundamental or indispensable functions in the cell. Here, we developed an approach to identifying the "essential lethality" arising from these mutated/deleted essential genes, which are largely tolerated in cancer cells due to genetic redundancy. We uncovered the cohesion subunit SA1 as a putative synthetic-essential target in cancers carrying inactivating mutations of its paralog, SA2. In SA2-deficient Ewing sarcoma and bladder cancer, further depletion of SA1 profoundly and specifically suppressed cancer cell proliferation, survival, and tumorigenic potential. Mechanistically, inhibition of SA1 in the SA2-mutated cells led to premature chromatid separation, dramatic extension of mitotic duration, and consequently, lethal failure of cell division. More importantly, depletion of SA1 rendered those SA2-mutated cells more susceptible to DNA damage, especially double-strand breaks (DSBs), due to reduced functionality of DNA repair. Furthermore, inhibition of SA1 sensitized the SA2-deficient cancer cells to PARP inhibitors in vitro and in vivo, providing a potential therapeutic strategy for patients with SA2-deficient tumors.
ST2 as checkpoint target for colorectal cancer immunotherapy
(American Society for Clinical Investigation, 2020-05-07) Jeught, Kevin Van der; Sun, Yifan; Fang, Yuanzhang; Zhou, Zhuolong; Jiang, Hua; Yu, Tao; Yang, Jinfeng; Kamocka, Malgorzata M.; So, Ka Man; Li, Yujing; Eyvani, Haniyeh; Sandusky, George E.; Frieden, Michael; Braun, Harald; Beyaert, Rudi; He, Xiaoming; Zhang, Xinna; Zhang, Chi; Paczesny, Sophie; Lu, Xiongbin; Pediatrics, School of Medicine
Immune checkpoint blockade immunotherapy delivers promising clinical results in colorectal cancer (CRC). However, only a fraction of cancer patients develop durable responses. The tumor microenvironment (TME) negatively impacts tumor immunity and subsequently clinical outcomes. Therefore, there is a need to identify other checkpoint targets associated with the TME. Early-onset factors secreted by stromal cells as well as tumor cells often help recruit immune cells to the TME, among which are alarmins such as IL-33. The only known receptor for IL-33 is stimulation 2 (ST2). Here we demonstrated that high ST2 expression is associated with poor survival and is correlated with low CD8+ T cell cytotoxicity in CRC patients. ST2 is particularly expressed in tumor-associated macrophages (TAMs). In preclinical models of CRC, we demonstrated that ST2-expressing TAMs (ST2+ TAMs) were recruited into the tumor via CXCR3 expression and exacerbated the immunosuppressive TME; and that combination of ST2 depletion using ST2-KO mice with anti–programmed death 1 treatment resulted in profound growth inhibition of CRC. Finally, using the IL-33trap fusion protein, we suppressed CRC tumor growth and decreased tumor-infiltrating ST2+ TAMs. Together, our findings suggest that ST2 could serve as a potential checkpoint target for CRC immunotherapy.
Targeting 17q23 amplicon to overcome the resistance to anti-HER2 therapy in HER2+ breast cancer
(Nature Research, 2018-11-09) Liu, Yunhua; Xu, Jiangsheng; Choi, Hyun Ho; Han, Cecil; Fang, Yuanzhang; Li, Yujing; Van der Jeught, Kevin; Xu, Hanchen; Zhang, Lu; Frieden, Michael; Wang, Lifei; Eyvani, Haniyeh; Sun, Yifan; Zhao, Gang; Zhang, Yuntian; Liu, Sheng; Wan, Jun; Huang, Cheng; Ji, Guang; Lu, Xiongbin; He, Xiaoming; Zhang, Xinna; Medical and Molecular Genetics, School of Medicine
Chromosome 17q23 amplification occurs in ~11% of human breast cancers. Enriched in HER2+ breast cancers, the 17q23 amplification is significantly correlated with poor clinical outcomes. In addition to the previously identified oncogene WIP1, we uncover an oncogenic microRNA gene, MIR21, in a majority of the WIP1-containing 17q23 amplicons. The 17q23 amplification results in aberrant expression of WIP1 and miR-21, which not only promotes breast tumorigenesis, but also leads to resistance to anti-HER2 therapies. Inhibiting WIP1 and miR-21 selectively inhibits the proliferation, survival and tumorigenic potential of the HER2+ breast cancer cells harboring 17q23 amplification. To overcome the resistance of trastuzumab-based therapies in vivo, we develop pH-sensitive nanoparticles for specific co-delivery of the WIP1 and miR-21 inhibitors into HER2+ breast tumors, leading to a profound reduction of tumor growth. These results demonstrate the great potential of the combined treatment of WIP1 and miR-21 inhibitors for the trastuzumab-resistant HER2+ breast cancers.

Browsing by Author "Fang, Yuanzhang"

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