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Article ; Online: Fc receptor-like 5 (FCRL5)-directed CAR-T cells exhibit antitumor activity against multiple myeloma

Zhengyu Yu / Hexian Li / Qizhong Lu / Zongliang Zhang / Aiping Tong / Ting Niu

Signal Transduction and Targeted Therapy, Vol 9, Iss 1, Pp 1-

2024 Volume 14

Abstract: Abstract Multiple myeloma (MM) remains a challenging hematologic malignancy despite advancements in chimeric antigen receptor T-cell (CAR-T) therapy. Current targets of CAR-T cells used in MM immunotherapy have limitations, with a subset of patients ... ...

Abstract	Abstract Multiple myeloma (MM) remains a challenging hematologic malignancy despite advancements in chimeric antigen receptor T-cell (CAR-T) therapy. Current targets of CAR-T cells used in MM immunotherapy have limitations, with a subset of patients experiencing antigen loss resulting in relapse. Therefore, novel targets for enhancing CAR-T cell therapy in MM remain needed. Fc receptor-like 5 (FCRL5) is a protein marker with considerably upregulated expression in MM and has emerged as a promising target for CAR-T cell therapeutic interventions, offering an alternative treatment for MM. To further explore this option, we designed FCRL5-directed CAR-T cells and assessed their cytotoxicity in vitro using a co-culture system and in vivo using MM cell-derived xenograft models, specifically focusing on MM with gain of chromosome 1q21. Given the challenges in CAR-T therapies arising from limited T cell persistence, our approach incorporates interleukin-15 (IL-15), which enhances the functionality of central memory T (TCM) cells, into the design of FCRL5-directed CAR-T cells, to improve cytotoxicity and reduce T-cell dysfunction, thereby promoting greater CAR-T cell survival and efficacy. Both in vitro and xenograft models displayed that FCRL5 CAR-T cells incorporating IL-15 exhibited potent antitumor efficacy, effectively inhibiting the proliferation of MM cells and leading to remarkable tumor suppression. Our results highlight the capacity of FCRL5-specific CAR-T cells with the integration of IL-15 to improve the therapeutic potency, suggesting a potential novel immunotherapeutic strategy for MM treatment.
Keywords	Medicine ; R ; Biology (General) ; QH301-705.5
Subject code	610
Language	English
Publishing date	2024-01-01T00:00:00Z
Publisher	Nature Publishing Group
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: Fc receptor-like 5 (FCRL5)-directed CAR-T cells exhibit antitumor activity against multiple myeloma.

Yu, Zhengyu / Li, Hexian / Lu, Qizhong / Zhang, Zongliang / Tong, Aiping / Niu, Ting

Signal transduction and targeted therapy

2024 Volume 9, Issue 1, Page(s) 16

Abstract: Multiple myeloma (MM) remains a challenging hematologic malignancy despite advancements in chimeric antigen receptor T-cell (CAR-T) therapy. Current targets of CAR-T cells used in MM immunotherapy have limitations, with a subset of patients experiencing ... ...

Abstract	Multiple myeloma (MM) remains a challenging hematologic malignancy despite advancements in chimeric antigen receptor T-cell (CAR-T) therapy. Current targets of CAR-T cells used in MM immunotherapy have limitations, with a subset of patients experiencing antigen loss resulting in relapse. Therefore, novel targets for enhancing CAR-T cell therapy in MM remain needed. Fc receptor-like 5 (FCRL5) is a protein marker with considerably upregulated expression in MM and has emerged as a promising target for CAR-T cell therapeutic interventions, offering an alternative treatment for MM. To further explore this option, we designed FCRL5-directed CAR-T cells and assessed their cytotoxicity in vitro using a co-culture system and in vivo using MM cell-derived xenograft models, specifically focusing on MM with gain of chromosome 1q21. Given the challenges in CAR-T therapies arising from limited T cell persistence, our approach incorporates interleukin-15 (IL-15), which enhances the functionality of central memory T (TCM) cells, into the design of FCRL5-directed CAR-T cells, to improve cytotoxicity and reduce T-cell dysfunction, thereby promoting greater CAR-T cell survival and efficacy. Both in vitro and xenograft models displayed that FCRL5 CAR-T cells incorporating IL-15 exhibited potent antitumor efficacy, effectively inhibiting the proliferation of MM cells and leading to remarkable tumor suppression. Our results highlight the capacity of FCRL5-specific CAR-T cells with the integration of IL-15 to improve the therapeutic potency, suggesting a potential novel immunotherapeutic strategy for MM treatment.
MeSH term(s)	Humans ; Multiple Myeloma/genetics ; Multiple Myeloma/therapy ; Receptors, Chimeric Antigen/genetics ; Interleukin-15/genetics ; Interleukin-15/metabolism ; Cell Line, Tumor ; T-Lymphocytes ; Receptors, Fc/metabolism
Chemical Substances	Receptors, Chimeric Antigen ; Interleukin-15 ; Receptors, Fc ; FCRL5 protein, human
Language	English
Publishing date	2024-01-12
Publishing country	England
Document type	Journal Article
ZDB-ID	2886872-9
ISSN	2059-3635 ; 2095-9907
ISSN (online)	2059-3635
ISSN	2095-9907
DOI	10.1038/s41392-023-01702-2
Database	MEDical Literature Analysis and Retrieval System OnLINE

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Article ; Online: Ubiquitin C-terminal hydrolase L1 (UCHL1), a double-edged sword in mammalian oocyte maturation and spermatogenesis.

Yang, Donghui / Lu, Qizhong / Peng, Sha / Hua, Jinlian

Cell proliferation

2022 Volume 56, Issue 2, Page(s) e13347

Abstract: Background: Recent studies have shown that ubiquitin-mediated cell apoptosis can modulate protein interaction and involve in the progress of oocyte maturation and spermatogenesis. As one of the key regulators involved in ubiquitin signal, ubiquitin C- ... ...

Abstract	Background: Recent studies have shown that ubiquitin-mediated cell apoptosis can modulate protein interaction and involve in the progress of oocyte maturation and spermatogenesis. As one of the key regulators involved in ubiquitin signal, ubiquitin C-terminal hydrolase L1 (UCHL1) is considered a molecular marker associated with spermatogonia stem cells. However, the function of UCHL1 was wildly reported to regulate various bioecological processes, such as Parkinson's disease, lung cancer, breast cancer and colon cancer, how UCHL1 affects the mammalian reproductive system remains an open question. Methods: We identified papers through electronic searches of PubMed database from inception to July 2022. Results: Here, we summarize the important function of UCHL1 in controlling mammalian oocyte development, regulating spermatogenesis and inhibiting polyspermy, and we posit the balance of UCHL1 was essential to maintaining reproductive cellular and tissue homeostasis. Conclusion: This study considers the 'double-edged sword' role of UCHL1 during gametogenesis and presents new insights into UCHL1 in germ cells.
MeSH term(s)	Male ; Animals ; Ubiquitin Thiolesterase/genetics ; Ubiquitin Thiolesterase/metabolism ; Spermatogenesis/physiology ; Germ Cells/metabolism ; Mammals/metabolism ; Ubiquitin/metabolism ; Oocytes/metabolism
Chemical Substances	Ubiquitin Thiolesterase (EC 3.4.19.12) ; Ubiquitin
Language	English
Publishing date	2022-10-11
Publishing country	England
Document type	Journal Article ; Review
ZDB-ID	1064202-x
ISSN	1365-2184 ; 0008-8730 ; 0960-7722
ISSN (online)	1365-2184
ISSN	0008-8730 ; 0960-7722
DOI	10.1111/cpr.13347
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Book ; Online: D$^2$ST-Adapter

Pei, Wenjie / Tan, Qizhong / Lu, Guangming / Tian, Jiandong

Disentangled-and-Deformable Spatio-Temporal Adapter for Few-shot Action Recognition

2023

Abstract: Adapting large pre-trained image models to few-shot action recognition has proven to be an effective and efficient strategy for learning robust feature extractors, which is essential for few-shot learning. Typical fine-tuning based adaptation paradigm is ...

Abstract	Adapting large pre-trained image models to few-shot action recognition has proven to be an effective and efficient strategy for learning robust feature extractors, which is essential for few-shot learning. Typical fine-tuning based adaptation paradigm is prone to overfitting in the few-shot learning scenarios and offers little modeling flexibility for learning temporal features in video data. In this work we present the Disentangled-and-Deformable Spatio-Temporal Adapter (D$^2$ST-Adapter), a novel adapter tuning framework for few-shot action recognition, which is designed in a dual-pathway architecture to encode spatial and temporal features in a disentangled manner. Furthermore, we devise the Deformable Spatio-Temporal Attention module as the core component of D$^2$ST-Adapter, which can be tailored to model both spatial and temporal features in corresponding pathways, allowing our D$^2$ST-Adapter to encode features in a global view in 3D spatio-temporal space while maintaining a lightweight design. Extensive experiments with instantiations of our method on both pre-trained ResNet and ViT demonstrate the superiority of our method over state-of-the-art methods for few-shot action recognition. Our method is particularly well-suited to challenging scenarios where temporal dynamics are critical for action recognition.
Keywords	Computer Science - Computer Vision and Pattern Recognition
Publishing date	2023-12-03
Publishing country	us
Document type	Book ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: Improved antitumor effects elicited by an oncolytic HSV-1 expressing a novel B7H3nb/CD3 BsAb.

Zhang, Zongliang / Yang, Nian / Lu, Huaqing / Chen, Yongdong / Xu, Long / Wang, Zeng / Lu, Qizhong / Zhong, Kunhong / Zhu, Zhixiong / Wang, Guoqing / Li, Hexian / Zheng, Meijun / Zhang, Weiwei / Yang, Hui / Peng, Xingchen / Zhou, Liangxue / Tong, Aiping

Cancer letters

2024 Volume 588, Page(s) 216760

Abstract: Oncolytic viruses have emerged as a promising modality for cancer treatment due to their unique abilities to directly destroy tumor cells and modulate the tumor microenvironment. Bispecific T-cell engagers (BsAbs) have been developed to activate and ... ...

Abstract	Oncolytic viruses have emerged as a promising modality for cancer treatment due to their unique abilities to directly destroy tumor cells and modulate the tumor microenvironment. Bispecific T-cell engagers (BsAbs) have been developed to activate and redirect cytotoxic T lymphocytes, enhancing the antitumor response. To take advantage of the specific infection capacity and carrying ability of exogenous genes, we generated a recombinant herpes simplex virus type 1 (HSV-1), HSV-1
MeSH term(s)	Humans ; Herpesvirus 1, Human/genetics ; CD8-Positive T-Lymphocytes ; Oncolytic Viruses/genetics ; Neoplasms/genetics ; Oncolytic Virotherapy/methods ; Tumor Microenvironment
Language	English
Publishing date	2024-02-29
Publishing country	Ireland
Document type	Journal Article
ZDB-ID	195674-7
ISSN	1872-7980 ; 0304-3835
ISSN (online)	1872-7980
ISSN	0304-3835
DOI	10.1016/j.canlet.2024.216760
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Article ; Online: A multi-omics analysis of viral nucleic acid poly(I:C) responses to mammalian testicular stimulation.

Yang, Donghui / Wu, Wenping / Lu, Qizhong / Mou, Yaling / Chen, Wenbo / Wan, Shicheng / Zhang, Mengfei / Wang, Congliang / Du, Xiaomin / Li, Na / Hua, Jinlian

Stress biology

2024 Volume 4, Issue 1, Page(s) 9

Abstract: The male reproductive system has a standard immune response regulatory mechanism, However, a variety of external stimuli, including viruses, bacteria, heat, and medications can damage the testicles and cause orchitis and epididymitis. It has been shown ... ...

Abstract	The male reproductive system has a standard immune response regulatory mechanism, However, a variety of external stimuli, including viruses, bacteria, heat, and medications can damage the testicles and cause orchitis and epididymitis. It has been shown that various RNA viruses are more likely to infect the testis than DNA viruses, inducing orchitis and impairing testicular function. It was found that local injection of the viral RNA analog poly(I:C) into the testes markedly disrupted the structure of the seminiferous tubules, accompanied by apoptosis and inflammation. Poly(I:C) mainly inhibited the expression of testosterone synthesis-associated proteins, STAR and MGARP, and affected the synthesis and metabolism of amino acids and lipids in the testis. This led to the disruption of the metabolite levels in the testis of mice, thus affecting the normal spermatogenesis process. The present study analyzed the acute inflammatory response of the testis to viral infection using a multi-omics approach. It provides insights into how RNA virus infection impairs testicular function and offers a theoretical basis for future studies on immune homeostasis and responses under stress conditions in male reproduction.
Language	English
Publishing date	2024-02-01
Publishing country	Switzerland
Document type	Journal Article
ISSN	2731-0450
ISSN (online)	2731-0450
DOI	10.1007/s44154-023-00146-6
Database	MEDical Literature Analysis and Retrieval System OnLINE

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Article ; Online: Delivery of CD47-SIRPα checkpoint blocker by BCMA-directed UCAR-T cells enhances antitumor efficacy in multiple myeloma.

Lu, Qizhong / Yang, Donghui / Li, Hexian / Zhu, Zhixiong / Zhang, Zongliang / Chen, Yongdong / Yang, Nian / Li, Jia / Wang, Zeng / Niu, Ting / Tong, Aiping

Cancer letters

2024 Volume 585, Page(s) 216660

Abstract: In the treatment of relapsed or refractory multiple myeloma patients, BCMA-directed autologous CAR-T cells have showed excellent anti-tumor activity. However, their widespread application is limited due to the arguably cost and time-consuming. Multiple ... ...

Abstract	In the treatment of relapsed or refractory multiple myeloma patients, BCMA-directed autologous CAR-T cells have showed excellent anti-tumor activity. However, their widespread application is limited due to the arguably cost and time-consuming. Multiple myeloma cells highly expressed CD47 molecule and interact with the SIRPα ligand on the surface of macrophages, in which evade the clearance of macrophages through the activation of "don't eat me" signal. In this study, a BCMA-directed universal CAR-T cells, BC404-UCART, secreting a CD47-SIRPα blocker was developed using CRISPR/Cas9 gene-editing system. BC404-UCART cells significantly inhibited tumor growth and prolonged the survival of mice in the xenograft model. The anti-tumor activity of BC404-UCART cells was achieved via two mechanisms, on the one hand, the UCAR-T cells directly killed tumor cells, on the other hand, the BC404-UCART cells enhanced the phagocytosis of macrophages by secreting anti-CD47 nanobody hu404-hfc fusion that blocked the "don't eat me" signal between macrophages and tumor cells, which provides a potential strategy for the development of novel "off-the-shelf" cellular immunotherapies for the treatment of multiple myeloma.
MeSH term(s)	Humans ; Mice ; Animals ; Multiple Myeloma/drug therapy ; Multiple Myeloma/genetics ; B-Cell Maturation Antigen ; CD47 Antigen/genetics ; Receptors, Immunologic/genetics ; T-Lymphocytes ; Antigens, Differentiation ; Neoplasms/pathology ; Phagocytosis
Chemical Substances	B-Cell Maturation Antigen ; CD47 Antigen ; Receptors, Immunologic ; Antigens, Differentiation ; CD47 protein, human
Language	English
Publishing date	2024-01-23
Publishing country	Ireland
Document type	Journal Article
ZDB-ID	195674-7
ISSN	1872-7980 ; 0304-3835
ISSN (online)	1872-7980
ISSN	0304-3835
DOI	10.1016/j.canlet.2024.216660
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Article ; Online: Influence of the Chemical Compositions of Bismuth Oxyiodides on the Electroreduction of Carbon Dioxide to Formate.

Wang, Qizhong / Ma, Meng / Zhang, Shuaishuai / Lu, Kangkang / Fu, Lijun / Liu, Xiaojing / Chen, Yuhui

ChemPlusChem

2020 Volume 85, Issue 4, Page(s) 672–678

Abstract: Bismuth oxyiodides with varying chemical compositions were fabricated to effectively electrochemical reduce ... ...

Abstract	Bismuth oxyiodides with varying chemical compositions were fabricated to effectively electrochemical reduce CO
Language	English
Publishing date	2020-03-19
Publishing country	Germany
Document type	Journal Article
ISSN	2192-6506
ISSN (online)	2192-6506
DOI	10.1002/cplu.202000131
Database	MEDical Literature Analysis and Retrieval System OnLINE

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Article ; Online: UCHL1 maintains microenvironmental homeostasis in goat germline stem cells.

Yang, Donghui / Zhang, Mengfei / Chen, Wenbo / Lu, Qizhong / Wan, Shicheng / Du, Xiaomin / Li, Yunxiang / Li, Balun / Wu, Wenping / Wang, Congliang / Li, Na / Peng, Sha / Tang, Haiyang / Hua, Jinlian

FASEB journal : official publication of the Federation of American Societies for Experimental Biology

2023 Volume 37, Issue 12, Page(s) e23306

Abstract: Spermatogonial stem cells (SSCs) play a crucial role in mammalian spermatogenesis and maintain the stable inheritance of the germline in livestock. However, stress and bacterial or viral infections can disrupt immune homeostasis of the testes, thereby ... ...

Abstract	Spermatogonial stem cells (SSCs) play a crucial role in mammalian spermatogenesis and maintain the stable inheritance of the germline in livestock. However, stress and bacterial or viral infections can disrupt immune homeostasis of the testes, thereby leading to spermatogenesis destruction and infertility, which severely affects the health and productivity of mammals. This study aimed to explore the effect of ubiquitin C-terminal hydrolase L1 (UCHL1) knockdown (KD) in goat SSCs and mouse testes and investigate the potential anti-inflammatory function of UCHL1 in a poly(I:C)-induced inflammation model to maintain microenvironmental homeostasis. In vitro, the downregulation of UCHL1 (UCHL1 KD) in goat SSCs increased the expression levels of apoptosis and inflammatory factors and inhibited the self-renewal and proliferation of SSCs. In vivo, the structure of seminiferous tubules and spermatogenic cells was disrupted after UCHL1 KD, and the expression levels of apoptosis- and inflammation-related proteins were significantly upregulated. Furthermore, UCHL1 inhibited the TLR3/TBK1/IRF3 pathway to resist poly(I:C)-induced inflammation in SSCs by antagonizing HSPA8 and thus maintaining SSC autoimmune homeostasis. Most importantly, the results of this study showed that UCHL1 maintained immune homeostasis of SSCs and spermatogenesis. UCHL1 KD not only inhibited the self-renewal and proliferation of goat SSCs and spermatogenesis but was also involved in the inflammatory response of goat SSCs. Additionally, UCHL1 has an antiviral function in SSCs by antagonizing HSPA8, which provides an important basis for exploring the specific mechanisms of UCHL1 in goat spermatogenesis.
MeSH term(s)	Animals ; Male ; Mice ; Goats ; Homeostasis ; Inflammation/metabolism ; Spermatogenesis/physiology ; Spermatogonia/metabolism ; Stem Cells ; Testis/metabolism
Language	English
Publishing date	2023-11-07
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	639186-2
ISSN	1530-6860 ; 0892-6638
ISSN (online)	1530-6860
ISSN	0892-6638
DOI	10.1096/fj.202301674RR
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Article ; Online: The Effective Combination of Humic Acid Phosphate Fertilizer Regulating the Form Transformation of Phosphorus and the Chemical and Microbial Mechanism of Its Phosphorus Availability

Xiong, Qizhong / Wang, Shaojie / Lu, Xuewei / Xu, Yating / Zhang, Lei / Chen, Xiaohui / Xu, Gang / Tian, Da / Zhang, Ligan / Jing, Jianyuan / Ye, Xinxin

Agronomy. 2023 June 11, v. 13, no. 6

2023

Abstract: In the process of phosphate fertilizer production, adding humic acid to produce humic-acid-value-added phosphate fertilizer can improve fertilizer efficiency and promote crop growth. Although studies have primarily focused on investigating the impact of ... ...

Abstract	In the process of phosphate fertilizer production, adding humic acid to produce humic-acid-value-added phosphate fertilizer can improve fertilizer efficiency and promote crop growth. Although studies have primarily focused on investigating the impact of humic acid’s structure and function on phosphorus availability in humic-acid-added phosphate fertilizers, there is limited research on the regulatory effects of phosphorus fertilizer structure and the synergistic mechanisms involving microorganisms. Therefore, this study aimed to examine the chemical and biological mechanisms underlying the increased efficiency of humic-acid-added phosphate fertilizers by implementing various treatment processes. These processes included physically blending humic acid with phosphate fertilizer (HA+P), chemically synthesizing humic acid phosphate fertilizer (HAP), using commercially available humic acid phosphate fertilizer (SHAP), employing ordinary potassium phosphate fertilizer (P), and implementing a control treatment with no phosphate fertilizer (CK). Investigating the synergistic mechanism of humic-acid-added phosphate fertilizers holds significant importance. The results showed that during the preparation of HAP at high temperature, a new absorption peak appeared at 1101 cm⁻¹, and a new chemical bond -O- was formed. The hydroxyl fracture in humic acid combined with phosphoric acid to form a phosphate ester (P-O-C=O) structure. HAP residues were concentrated on the surface and loaded with more soil minerals. The content of highly active oxygen-containing functional groups—such as aromatic C-O, carboxyl/amide carbon and carbonyl carbon—increased significantly, while the content of alkyl carbon, oxyalkyl carbon, and aromatic carbon decreased. Upon combining humic acid with potassium phosphate, the carboxyl group and calcium ions formed the HA-m-P complex, increasing the content of soluble phosphate (H₂PO₄⁻) in the soil by 1.71%. Compared to HA+P treatment, HAP treatment significantly increased the soil’s available P content by 13.8–47.7% (P < 0.05). The plant height, stem diameter, and above-ground biomass of HAP treatment were increased by 21.3%, 15.31%, and 61.02%, respectively, and the total accumulations of N, P, and K nutrient elements were increased by 6.71%, 31.13%, and 41.40%, respectively, compared to the control treatment. The results of high-throughput sequencing showed that the rhizosphere soil of HA+P and HAP treatment was rich in bacterial groups, the soil microbial structure was changed, and the bacterial community diversity was increased under HAP treatment. The number of genes encoding phytase and alkaline phosphatase associated with organophosphorus dissolution increased by 3.23% and 2.90%, respectively, in HAP treatment. Humic acid phosphate fertilizer forms phosphate esters in the process of chemical preparation. After application, the soil’s microbial community structure is changed, and soil enzyme activity related to phosphorus transformation is improved to promote tomatoes’ absorption of soil nutrients, thus promoting tomato plant growth and nutrient accumulation.
Keywords	aboveground biomass ; absorption ; agronomy ; alkaline phosphatase ; bacterial communities ; calcium ; carbon ; community structure ; enzyme activity ; humic acids ; phosphoric acid ; phosphorus ; phosphorus fertilizers ; phytases ; plant growth ; plant height ; potassium phosphates ; rhizosphere ; soil ; soil enzymes ; soluble phosphates ; temperature ; tomatoes
Language	English
Dates of publication	2023-0611
Publishing place	Multidisciplinary Digital Publishing Institute
Document type	Article ; Online
ZDB-ID	2607043-1
ISSN	2073-4395
ISSN	2073-4395
DOI	10.3390/agronomy13061581
Database	NAL-Catalogue (AGRICOLA)

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