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Sun L, Zhao Q, Ao S, Liu T, Wang Z, You J, Mi Z, Sun Y, Xue X, Ogese MO, Gardner J, Meng X, Naisbitt DJ, Liu H, Zhang F. Feedback regulation of VISTA and Treg by TNF-α controls T cell responses in drug allergy. Allergy 2025; 80:1400-1416. [PMID: 39526799 DOI: 10.1111/all.16393] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/17/2024] [Revised: 10/08/2024] [Accepted: 10/16/2024] [Indexed: 11/16/2024]
Abstract
BACKGROUND Severe cutaneous adverse reactions (SCARs) mediated by cytotoxic T lymphocytes are a series of life-threatening conditions with a mortality of 4%-20%. The clinical application of tumor necrosis factor-alpha (TNF-α) antagonist improves the outcome of some SCARs patients; however, this is complicated by the elusive and varied immunopathogenesis. METHODS To clarify the precise process and optimize the therapy regimen of SCARs, we performed single-cell sequencing, in vitro functional and clinical analysis of patients with SCARs. RESULTS We observed that TNF-α breaks drug-specific T-cell tolerance by inhibiting the expression of V-type immunoglobulin domain-containing suppressor of T-cell activation (VISTA). Furthermore, TNF-α generated a positive feedback loop in the early phase of drug-specific T-cell activation, whereby B cells acted reciprocally on the corresponding T cells to reinforce TNF-α cytokine expression. In contrast, this pathway of TNF-α-VISTA signaling did not operate in memory effector T cells. Drug-specific memory effector T-cell responses were inhibited by increasing Treg cell expression in a negative feedback loop, with TNF-α antagonists preventing the inhibitory effect. These observations align with the clinical analysis that early but not late intervention with TNF-α antagonists significantly improved outcomes in SCARs patients. CONCLUSION Our findings defining feedback regulation of VISTA and Treg cells by TNF-α in different stages of the drug-specific T-cell response and, indicate that a Treg agonists, instead of TNF-α antagonists, could be used for treatment of patients with progressive SCARs.
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Affiliation(s)
- Lele Sun
- Hospital for Skin Diseases, Shandong First Medical University, Jinan, Shandong, China
- Shandong Provincial Institute of Dermatology and Venereology, Shandong Academy of Medical Sciences, Jinan, Shandong, China
| | - Qing Zhao
- Hospital for Skin Diseases, Shandong First Medical University, Jinan, Shandong, China
- Shandong Provincial Institute of Dermatology and Venereology, Shandong Academy of Medical Sciences, Jinan, Shandong, China
| | - Suiting Ao
- Hospital for Skin Diseases, Shandong First Medical University, Jinan, Shandong, China
- Shandong Provincial Institute of Dermatology and Venereology, Shandong Academy of Medical Sciences, Jinan, Shandong, China
| | - Tingting Liu
- Hospital for Skin Diseases, Shandong First Medical University, Jinan, Shandong, China
- Shandong Provincial Institute of Dermatology and Venereology, Shandong Academy of Medical Sciences, Jinan, Shandong, China
| | - Zhenzhen Wang
- Hospital for Skin Diseases, Shandong First Medical University, Jinan, Shandong, China
- Shandong Provincial Institute of Dermatology and Venereology, Shandong Academy of Medical Sciences, Jinan, Shandong, China
| | - Jiabao You
- Hospital for Skin Diseases, Shandong First Medical University, Jinan, Shandong, China
- Shandong Provincial Institute of Dermatology and Venereology, Shandong Academy of Medical Sciences, Jinan, Shandong, China
| | - Zihao Mi
- Hospital for Skin Diseases, Shandong First Medical University, Jinan, Shandong, China
- Shandong Provincial Institute of Dermatology and Venereology, Shandong Academy of Medical Sciences, Jinan, Shandong, China
| | - Yonghu Sun
- Hospital for Skin Diseases, Shandong First Medical University, Jinan, Shandong, China
- Shandong Provincial Institute of Dermatology and Venereology, Shandong Academy of Medical Sciences, Jinan, Shandong, China
| | - Xiaotong Xue
- Hospital for Skin Diseases, Shandong First Medical University, Jinan, Shandong, China
- Shandong Provincial Institute of Dermatology and Venereology, Shandong Academy of Medical Sciences, Jinan, Shandong, China
| | - Monday O Ogese
- MRC Centre for Drug Safety Science, Department of Pharmacology and Therapeutic, Institute of Systems, Molecular and Integrative Biology, University of Liverpool, Liverpool, UK
| | - Joshua Gardner
- MRC Centre for Drug Safety Science, Department of Pharmacology and Therapeutic, Institute of Systems, Molecular and Integrative Biology, University of Liverpool, Liverpool, UK
| | - Xiaoli Meng
- MRC Centre for Drug Safety Science, Department of Pharmacology and Therapeutic, Institute of Systems, Molecular and Integrative Biology, University of Liverpool, Liverpool, UK
| | - Dean J Naisbitt
- MRC Centre for Drug Safety Science, Department of Pharmacology and Therapeutic, Institute of Systems, Molecular and Integrative Biology, University of Liverpool, Liverpool, UK
| | - Hong Liu
- Hospital for Skin Diseases, Shandong First Medical University, Jinan, Shandong, China
- Shandong Provincial Institute of Dermatology and Venereology, Shandong Academy of Medical Sciences, Jinan, Shandong, China
- School of Public Health, Shandong First Medical University and Shandong Academy of Medical Sciences, Jinan, China
| | - Furen Zhang
- Hospital for Skin Diseases, Shandong First Medical University, Jinan, Shandong, China
- Shandong Provincial Institute of Dermatology and Venereology, Shandong Academy of Medical Sciences, Jinan, Shandong, China
- School of Public Health, Shandong First Medical University and Shandong Academy of Medical Sciences, Jinan, China
- Shandong University of Traditional Chinese Medicine, Jinan, Shandong, China
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Zhou Q, Yang T, Yu X, Li B, Liu J, Mao Y, Guo R, Feng Z, Zhou L, Zeng G, Li N, Liang J, Liu L, Feng P, Shu HB, Chen L. Lanatoside C activates the E3 ligase STUB1 to inhibit FOXP3 transcriptional activity and promote antitumor immunity. EMBO Mol Med 2025; 17:563-588. [PMID: 39979425 PMCID: PMC11904033 DOI: 10.1038/s44321-025-00200-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/06/2024] [Revised: 12/29/2024] [Accepted: 02/03/2025] [Indexed: 02/22/2025] Open
Abstract
Regulatory T cells (Tregs) play critical roles in inhibiting antitumor immunity, which is dependent on FOXP3-mediated transcriptional activity. However, no Treg-specific therapeutics has been approved for clinical use. We performed a high-throughput screen of FDA-approved drugs for potential inhibitors of FOXP3 transcriptional activity. These efforts identified Lanatoside C (Lac), which potently inhibits FOXP3 activity by causing degradation of RUNX1, a FOXP3-associated component required for its transcriptional activity. Lac directly binds the E3 ligase STUB1, leading to increased polyubiquitination and proteasomal degradation of RUNX1. Lac inhibits Tregs activity and promotes antitumor immunity in a mouse primary lung cancer model. In addition, Lac synergizes with PD-1 inhibitor to shrink lung cancers driven by mutant KRAS in a mouse model. Our findings suggested that the FDA-approved Lac is a Tregs inhibitor and serves as a candidate drug for cancer patients by its own or in combination with existing therapeutics such as PD-1 inhibitors.
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Affiliation(s)
- Qian Zhou
- State Key Laboratory of Bioactive Molecules and Druggability Assessment, Guangdong Basic Research Center of Excellence for Natural Bioactive Molecules and Discovery of Innovative Drugs, College of Life Science and Technology, Jinan University, 510006, Guangzhou, China.
| | - Tong Yang
- State Key Laboratory of Bioactive Molecules and Druggability Assessment, Guangdong Basic Research Center of Excellence for Natural Bioactive Molecules and Discovery of Innovative Drugs, College of Life Science and Technology, Jinan University, 510006, Guangzhou, China
| | - Xixi Yu
- State Key Laboratory of Bioactive Molecules and Druggability Assessment, Guangdong Basic Research Center of Excellence for Natural Bioactive Molecules and Discovery of Innovative Drugs, College of Life Science and Technology, Jinan University, 510006, Guangzhou, China
| | - Bo Li
- MOE Key Laboratory of Glucolipid Metabolic Diseases, Guangdong Metabolic Diseases Research Center of Integrated Chinese and Western Medicine, College of Chinese Medicine Research, Guangdong Pharmaceutical University, 510006, Guangzhou, China
| | - Jin Liu
- State Key Laboratory of Bioactive Molecules and Druggability Assessment, Guangdong Basic Research Center of Excellence for Natural Bioactive Molecules and Discovery of Innovative Drugs, College of Life Science and Technology, Jinan University, 510006, Guangzhou, China
| | - Yongxin Mao
- MOE Key Laboratory of Glucolipid Metabolic Diseases, Guangdong Metabolic Diseases Research Center of Integrated Chinese and Western Medicine, College of Chinese Medicine Research, Guangdong Pharmaceutical University, 510006, Guangzhou, China
| | - Rongxiang Guo
- State Key Laboratory of Bioactive Molecules and Druggability Assessment, Guangdong Basic Research Center of Excellence for Natural Bioactive Molecules and Discovery of Innovative Drugs, College of Life Science and Technology, Jinan University, 510006, Guangzhou, China
| | - Zhuo Feng
- State Key Laboratory of Bioactive Molecules and Druggability Assessment, Guangdong Basic Research Center of Excellence for Natural Bioactive Molecules and Discovery of Innovative Drugs, College of Life Science and Technology, Jinan University, 510006, Guangzhou, China
| | - Li Zhou
- MOE Key Laboratory of Glucolipid Metabolic Diseases, Guangdong Metabolic Diseases Research Center of Integrated Chinese and Western Medicine, College of Chinese Medicine Research, Guangdong Pharmaceutical University, 510006, Guangzhou, China
| | - Guandi Zeng
- State Key Laboratory of Bioactive Molecules and Druggability Assessment, Guangdong Basic Research Center of Excellence for Natural Bioactive Molecules and Discovery of Innovative Drugs, College of Life Science and Technology, Jinan University, 510006, Guangzhou, China
| | - Nan Li
- State Key Laboratory of Bioactive Molecules and Druggability Assessment, Guangdong Basic Research Center of Excellence for Natural Bioactive Molecules and Discovery of Innovative Drugs, College of Life Science and Technology, Jinan University, 510006, Guangzhou, China
| | - Jinxia Liang
- State Key Laboratory of Bioactive Molecules and Druggability Assessment, Guangdong Basic Research Center of Excellence for Natural Bioactive Molecules and Discovery of Innovative Drugs, College of Life Science and Technology, Jinan University, 510006, Guangzhou, China
| | - Lu Liu
- State Key Laboratory of Bioactive Molecules and Druggability Assessment, Guangdong Basic Research Center of Excellence for Natural Bioactive Molecules and Discovery of Innovative Drugs, College of Life Science and Technology, Jinan University, 510006, Guangzhou, China
| | - Pengju Feng
- Department of Chemistry, College of Chemistry and Materials Science, Jinan University Guangzhou, 510632, Guangzhou, China
| | - Hong-Bing Shu
- Department of Infectious Diseases, Medical Research Institute, Zhongnan Hospital of Wuhan University, Wuhan University, 430073, Wuhan, China.
| | - Liang Chen
- State Key Laboratory of Bioactive Molecules and Druggability Assessment, Guangdong Basic Research Center of Excellence for Natural Bioactive Molecules and Discovery of Innovative Drugs, College of Life Science and Technology, Jinan University, 510006, Guangzhou, China.
- MOE Key Laboratory of Tumor Molecular Biology and Key Laboratory of Functional Protein Research of Guangdong Higher Education Institutes, Institute of Life and Health Engineering, College of Life Science and Technology, Jinan University, 510632, Guangzhou, China.
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Okano S. Immunotherapy for head and neck cancer: Fundamentals and therapeutic development. Auris Nasus Larynx 2024; 51:684-695. [PMID: 38729034 DOI: 10.1016/j.anl.2024.05.001] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/26/2023] [Revised: 04/03/2024] [Accepted: 05/01/2024] [Indexed: 05/12/2024]
Abstract
Squamous cell carcinoma of the head and neck (SCCHN) has been treated by multidisciplinary therapy consisting of surgery, radiotherapy, and cancer chemotherapy, but the recent advent of immunotherapy has produced significant changes in treatment systems and the results of these therapies. Immunotherapy has greatly improved the outcome of recurrent metastatic SCCHN, and the development of new treatment methods based on immunotherapy is now being applied not only to recurrent metastatic cases but also to locally advanced cases. To understand and practice cancer immunotherapy, it is important to understand the immune environment surrounding cancer, and the changes to which it is subject. Currently, the anti-PD-1 antibody drugs nivolumab and pembrolizumab are the only immunotherapies with proven efficacy in head and neck cancer. However, anti-PD-L1 and anti-CTLA-4 antibody drugs have also been shown to be useful in other types of cancer and are being incorporated into clinical practice. In head and neck cancer, numerous clinical trials have aimed to improve efficacy and safety by combining immunotherapy with other drug therapies and treatment modalities. Combinations of immunotherapy with cancer drugs with different mechanisms of action (cytotoxic agents, molecular-targeted agents, immune checkpoint inhibitors), as well as with radiation therapy and surgery are being investigated, and have the potential to significantly change medical care for these patients. The application of cancer immunotherapy not only to daily clinical practice but also to further therapeutic development requires a clear and complete understanding of the fundamentals of cancer immunotherapy, and knowledge of the numerous clinical studies conducted, both past and present. The results of these trials are numerous, both positive and negative, and a comprehensive understanding of this wide range of completed and ongoing clinical trials is critical to a systematic and comprehensive understanding of their scope and lessons learnt. In this article, after outlining the concepts of ``cancer immune cycle,'' ``cancer immune editing,'' and ``tumor microenvironment'' to provide an understanding of the basics of cancer immunity, we summarize the basics and clinical trial data on representative immune checkpoint inhibitors used in various cancer types, as well as recent therapeutic developments in cancer immunotherapy and the current status of these new treatments.
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Affiliation(s)
- Susumu Okano
- Department of Head and Neck Medical Oncology, National Cancer Center Hospital East, 6-5-1, Kashiwanoha, Kashiwa, Chiba 277-8577, Japan.
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Cao W, He Y, Lan J, Luo S, Sun B, Xiao C, Yu W, Zeng Z, Lei S. FOXP3 promote the progression of glioblastoma via inhibiting ferroptosis mediated by linc00857/miR-1290/GPX4 axis. Cell Death Dis 2024; 15:239. [PMID: 38561331 PMCID: PMC10984987 DOI: 10.1038/s41419-024-06619-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/14/2023] [Revised: 03/14/2024] [Accepted: 03/18/2024] [Indexed: 04/04/2024]
Abstract
The oncogenic properties of members belonging to the forkhead box (FOX) family have been extensively documented in different types of cancers. In this study, our objective was to investigate the impact of FOXP3 on glioblastoma multiforme (GBM) cells. By conducting a screen using a small hairpin RNA (shRNA) library, we discovered a significant association between FOXP3 and ferroptosis in GBM cells. Furthermore, we observed elevated levels of FOXP3 in both GBM tissues and cell lines, which correlated with a poorer prognosis. FOXP3 was found to promote the proliferation of GBM cells by inhibiting cell ferroptosis in vitro and in vivo. Mechanistically, FOXP3 not only directly upregulated the transcription of GPX4, but also attenuated the degradation of GPX4 mRNA through the linc00857/miR-1290 axis, thereby suppressing ferroptosis and promoting proliferation. Additionally, the FOXP3 inhibitor epirubicin exhibited the ability to impede proliferation and induce ferroptosis in GBM cells both in vitro and in vivo. In summary, our study provided evidences that FOXP3 facilitates the progression of glioblastoma by inhibiting ferroptosis via the linc00857/miR-1290/GPX4 axis, highlighting FOXP3 as a potential therapeutic target for GBM.
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Affiliation(s)
- Wenpeng Cao
- Department of Anatomy, School of Basic Medicine, Guizhou Medical University, Guiyang, 550009, Guizhou, China.
| | - Ya He
- Key Laboratory of Pathogenesis and Drug Research on Common Chronic Diseases, Guizhou Medical University, Guiyang, 550009, Guizhou, China
| | - Jinzhi Lan
- Key Laboratory of Pathogenesis and Drug Research on Common Chronic Diseases, Guizhou Medical University, Guiyang, 550009, Guizhou, China
| | - Shipeng Luo
- Department of Anatomy, School of Basic Medicine, Guizhou Medical University, Guiyang, 550009, Guizhou, China
| | - Baofei Sun
- Department of Anatomy, School of Basic Medicine, Guizhou Medical University, Guiyang, 550009, Guizhou, China
- Key Laboratory of Endemic and Ethnic Diseases, Ministry of Education, School of Basic Medicine, Guizhou Medical University, Guiyang, 550009, Guizhou, China
| | - Chaolun Xiao
- Department of Anatomy, School of Basic Medicine, Guizhou Medical University, Guiyang, 550009, Guizhou, China
| | - Wenfeng Yu
- Key Laboratory of Endemic and Ethnic Diseases, Ministry of Education, School of Basic Medicine, Guizhou Medical University, Guiyang, 550009, Guizhou, China
- Key Laboratory of Endemic and Ethnic Diseases, Ministry of Education, Guizhou Medical University, Guiyang, 550009, Guizhou, China
- Key Laboratory of Medical Molecular Biology, School of Basic Medicine, Guizhou Medical University, Guiyang, 550009, China
| | - Zhirui Zeng
- Key Laboratory of Pathogenesis and Drug Research on Common Chronic Diseases, Guizhou Medical University, Guiyang, 550009, Guizhou, China.
| | - Shan Lei
- Key Laboratory of Pathogenesis and Drug Research on Common Chronic Diseases, Guizhou Medical University, Guiyang, 550009, Guizhou, China.
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Zhang Y, Zhang Z, Li H, Chu C, Liang G, Fan N, Wei R, Zhang T, Li L, Wang B, Li X. Increased miR-6132 promotes deep vein thrombosis formation by downregulating FOXP3 expression. Front Cardiovasc Med 2024; 11:1356286. [PMID: 38572308 PMCID: PMC10987872 DOI: 10.3389/fcvm.2024.1356286] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/15/2023] [Accepted: 03/08/2024] [Indexed: 04/05/2024] Open
Abstract
Background Deep vein thrombosis (DVT) is associated with aberrant gene expression that is a common peripheral vascular disease. Here, we aimed to elucidate that the epigenetic modification of forkhead box protein 3 (FOXP3) at the post-transcriptional level, which might be the key trigger leading to the down-regulation of FOXP3 expression in DVT. Methods In order to explore the relationship between microRNAs (miRNAs) and FOXP3, mRNA and microRNA microarray analysis were performed. Dual luciferase reporter assay was used to verify the upstream miRNAs of FOXP3. Quantitative real-time polymerase chain reaction, flow cytometry and Western blot were used to detect the relative expression of miR-6132 and FOXP3. Additionally, DVT models were established to investigate the role of miR-6132 by Murine Doppler Ultrasound and Hematoxylin-Eosin staining. Results Microarray and flow cytometry results showed that the FOXP3 expression was decreased while miR-6132 level was increased substantially in DVT, and there was significant negative correlation between miR-6132 and FOXP3. Moreover, we discovered that overexpressed miR-6132 reduced FOXP3 expression and aggravated DVT formation, while miR-6132 knockdown increased FOXP3 expression and alleviated DVT formation. Dual luciferase reporter assay validated the direct binding of miR-6132 to FOXP3. Conclusion Collectively, our data elucidate a new avenue through which up-regulated miR-6132 contributes to the formation and progression of DVT by inhibiting FOXP3 expression.
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Affiliation(s)
- Yunhong Zhang
- Innovative Institute of Chinese Medicine and Pharmacy, Shandong University of Traditional Chinese Medicine, Jinan, Shandong Province, China
| | - Zhen Zhang
- Innovative Institute of Chinese Medicine and Pharmacy, Shandong University of Traditional Chinese Medicine, Jinan, Shandong Province, China
| | - Haoyang Li
- International Business School, Tianjin Foreign Studies University, Tianjin, China
| | - Chu Chu
- Innovative Institute of Chinese Medicine and Pharmacy, Shandong University of Traditional Chinese Medicine, Jinan, Shandong Province, China
| | - Gang Liang
- Department of Peripheral Vascular Disease, Affiliated Hospital of Shandong University of Traditional Chinese Medicine, Jinan, Shandong Province, China
| | - Nannan Fan
- Innovative Institute of Chinese Medicine and Pharmacy, Shandong University of Traditional Chinese Medicine, Jinan, Shandong Province, China
| | - Ran Wei
- Innovative Institute of Chinese Medicine and Pharmacy, Shandong University of Traditional Chinese Medicine, Jinan, Shandong Province, China
- School of Clinical and Basic Medical Sciences, Shandong First Medical University& Shandong Academy of Medical Sciences, Jinan, Shandong Province, China
| | - Tingting Zhang
- Innovative Institute of Chinese Medicine and Pharmacy, Shandong University of Traditional Chinese Medicine, Jinan, Shandong Province, China
| | - Lihua Li
- Innovative Institute of Chinese Medicine and Pharmacy, Shandong University of Traditional Chinese Medicine, Jinan, Shandong Province, China
- School of Clinical and Basic Medical Sciences, Shandong First Medical University& Shandong Academy of Medical Sciences, Jinan, Shandong Province, China
| | - Bin Wang
- Department of Peripheral Vascular Disease, Affiliated Hospital of Shandong University of Traditional Chinese Medicine, Jinan, Shandong Province, China
| | - Xia Li
- Innovative Institute of Chinese Medicine and Pharmacy, Shandong University of Traditional Chinese Medicine, Jinan, Shandong Province, China
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Wang KL, Chen KD, Tang WW, Chen ZP, Wang YJ, Shi GP, Chen YG. Predicting colorectal cancer prognosis based on long noncoding RNAs of disulfidptosis genes. World J Clin Oncol 2024; 15:89-114. [PMID: 38292658 PMCID: PMC10823938 DOI: 10.5306/wjco.v15.i1.89] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/25/2023] [Revised: 12/17/2023] [Accepted: 01/04/2024] [Indexed: 01/23/2024] Open
Abstract
BACKGROUND A recently hypothesized cause of cell death called disulfidptosis has been linked to the expansion, emigration, and vascular rebuilding of cancer cells. Cancer can be treated by targeting the pathways that trigger cell death. AIM To discover the long non-coding RNA of the disulfidaptosis-related lncRNAs (DRLs), prognosis clinical survival, and treat patients with colorectal cancer with medications. METHODS Initially, we queried the Cancer Genome Atlas database to collect transcriptome, clinical, and genetic mutation data for colorectal cancer (CRC). Training and testing sets for CRC patient transcriptome data were generated randomly. Key long non-coding RNAs (lncRNAs) related to DRLs were then identified and evaluated using a least absolute shrinkage and selection operator procedure, as well as univariate and multivariate Cox regression models. A prognostic model was then created after risk scoring. Also, Immune infiltration analysis, immune checkpoint analysis, and medication susceptibility analysis were used to investigate the causes of the different prognoses between high and low risk groups. Finally, we validated the differential expression and biomarker potential of risk-predictive lncRNAs through induction using both NCM460 and HT-29 cell lines, as well as a disulfidptosis model. RESULTS In this work, eight significant lncRNAs linked to disulfidptosis were found. Gene ontology and Kyoto Encyclopedia of Genes and Genomes pathway enrichment analyses of differentially expressed genes between high- and low-risk groups from the prognostic model showed a close relationship with the immune response as well as significant enrichment in neutrophil extracellular trap formation and the IL-17 signaling pathway. Furthermore, significant immune cell variations between the high-risk and low-risk groups were seen, as well as a higher incidence of immunological escape risk in the high-risk group. Finally, Epirubicin, bortezomib, teniposide, and BMS-754807 were shown to have the lowest sensitivity among the four immunotherapy drugs. CONCLUSION Our findings emphasizes the role of disulfidptosis in regulating tumor development, therapeutic response, and patient survival in CRC patients. For the clinical treatment of CRC, these important LncRNAs could serve as viable therapeutic targets.
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Affiliation(s)
- Kui-Ling Wang
- Department of Colorectal Surgery, The Affiliated Hospital of Nanjing University of Chinese Medicine, Nanjing 210029, Jiangsu Province, China
| | - Kai-Di Chen
- Department of Colorectal Surgery, The Affiliated Hospital of Nanjing University of Chinese Medicine, Nanjing 210029, Jiangsu Province, China
| | - Wen-Wen Tang
- Department of Colorectal Surgery, The Affiliated Hospital of Nanjing University of Chinese Medicine, Nanjing 210029, Jiangsu Province, China
| | - Ze-Peng Chen
- Department of Colorectal Surgery, The Affiliated Hospital of Nanjing University of Chinese Medicine, Nanjing 210029, Jiangsu Province, China
| | - Yu-Ji Wang
- Department of Colorectal Surgery, The Affiliated Hospital of Nanjing University of Chinese Medicine, Nanjing 210029, Jiangsu Province, China
| | - Guo-Ping Shi
- Department of Colorectal Surgery, The Affiliated Hospital of Nanjing University of Chinese Medicine, Nanjing 210029, Jiangsu Province, China
| | - Yu-Gen Chen
- Department of Colorectal Surgery, The Affiliated Hospital of Nanjing University of Chinese Medicine, Nanjing 210029, Jiangsu Province, China
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Takahashi H, Miyoshi N, Murakami H, Okamura Y, Ogo N, Takagi A, Muraoka D, Asai A. Combined therapeutic effect of YHO-1701 with PD-1 blockade is dependent on natural killer cell activity in syngeneic mouse models. Cancer Immunol Immunother 2023; 72:2473-2482. [PMID: 37017695 PMCID: PMC10992562 DOI: 10.1007/s00262-023-03440-4] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/24/2022] [Accepted: 03/27/2023] [Indexed: 04/06/2023]
Abstract
The signal transducer and activator of transcription 3 (STAT3) signaling pathway is a key mediator of cancer cell proliferation, survival, and invasion. We discovered YHO-1701 as a small molecule inhibitor of STAT3 dimerization and demonstrated its potent anti-tumor activity using xenograft mouse models as monotherapy and combination therapy with molecular targeted drugs. STAT3 is also associated with cancer immune tolerance; therefore, we used the female CT26 syngeneic mouse model to examine the effect of combining YHO-1701 administration with PD-1/PD-L1 blockade. Pretreatment of the mice with YHO-1701 before starting anti-PD-1 antibody administration resulted in a significant therapeutic effect. In addition, the effect of monotherapy and combination treatment with YHO-1701 was significantly abolished by depleting natural killer (NK) cell activity. YHO-1701 was also found to restore the activity of mouse NK cells under inhibitory conditions in vitro. Furthermore, this combination therapy significantly inhibited tumor growth in an immunotherapy-resistant model of murine CMS5a fibrosarcoma. These results suggest that the combination of YHO-1701 with PD-1/PD-L1 blockade might be a new candidate for cancer immunotherapy involving the enhancement of NK cell activity in the tumor microenvironment.
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Affiliation(s)
- Hiroyuki Takahashi
- Center for Drug Discovery, Graduate School of Pharmaceutical Sciences, University of Shizuoka, 52-1 Yada, Suruga-Ku, Shizuoka-Shi, Shizuoka, 422-8526, Japan
- Pharmaceutical Research and Development Division, Yakult Honsha Co., Ltd, Tokyo, Japan
| | - Nao Miyoshi
- Center for Drug Discovery, Graduate School of Pharmaceutical Sciences, University of Shizuoka, 52-1 Yada, Suruga-Ku, Shizuoka-Shi, Shizuoka, 422-8526, Japan
| | - Hisashi Murakami
- Center for Drug Discovery, Graduate School of Pharmaceutical Sciences, University of Shizuoka, 52-1 Yada, Suruga-Ku, Shizuoka-Shi, Shizuoka, 422-8526, Japan
| | - Yuta Okamura
- Pharmaceutical Research and Development Division, Yakult Honsha Co., Ltd, Tokyo, Japan
| | - Naohisa Ogo
- Center for Drug Discovery, Graduate School of Pharmaceutical Sciences, University of Shizuoka, 52-1 Yada, Suruga-Ku, Shizuoka-Shi, Shizuoka, 422-8526, Japan
| | - Akimitsu Takagi
- Yakult Central Institute, Yakult Honsha Co., Ltd, Tokyo, Japan
| | - Daisuke Muraoka
- Division of Translational Oncoimmunology, Aichi Cancer Research Institute, Naogya, Japan
| | - Akira Asai
- Center for Drug Discovery, Graduate School of Pharmaceutical Sciences, University of Shizuoka, 52-1 Yada, Suruga-Ku, Shizuoka-Shi, Shizuoka, 422-8526, Japan.
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Liu N, Zhang R, Shi Q, Jiang H, Zhou Q. Intelligent delivery system targeting PD-1/PD-L1 pathway for cancer immunotherapy. Bioorg Chem 2023; 136:106550. [PMID: 37121105 DOI: 10.1016/j.bioorg.2023.106550] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/15/2023] [Revised: 04/11/2023] [Accepted: 04/13/2023] [Indexed: 05/02/2023]
Abstract
The drugs targeting the PD-1/PD-L1 pathway have gained abundant clinical applications for cancer immunotherapy. However, only a part of patients benefit from such immunotherapy. Thus, brilliant novel tactic to increase the response rate of patients is on the agenda. Nanocarriers, particularly the rationally designed intelligent delivery systems with controllable therapeutic agent release ability and improved tumor targeting capacity, are firmly recommended. In light of this, state-of-the-art nanocarriers that are responsive to tumor-specific microenvironments (internal stimuli, including tumor acidic microenvironment, high level of GSH and ROS, specifically upregulated enzymes) or external stimuli (e.g., light, ultrasound, radiation) and release the target immunomodulators at tumor sites feature the advantages of increased anti-tumor potency but decreased off-target toxicity. Given the fantastic past achievements and the rapid developments in this field, the future is promising. In this review, intelligent delivery platforms targeting the PD-1/PD-L1 axis are attentively appraised. Specifically, mechanisms of the action of these stimuli-responsive drug release platforms are summarized to raise some guidelines for prior PD-1/PD-L1-based nanocarrier designs. Finally, the conclusion and outlook in intelligent delivery system targeting PD-1/PD-L1 pathway for cancer immunotherapy are outlined.
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Affiliation(s)
- Ning Liu
- The Affiliated Hospital of Qingdao University, Qingdao University, Qingdao 266071, China; Cancer Institute, Qingdao University, Qingdao 266071, China
| | - Renshuai Zhang
- The Affiliated Hospital of Qingdao University, Qingdao University, Qingdao 266071, China; Cancer Institute, Qingdao University, Qingdao 266071, China
| | - Qiang Shi
- Moji-Nano Technology Co. Ltd., Yantai 264006, China
| | - Hongfei Jiang
- The Affiliated Hospital of Qingdao University, Qingdao University, Qingdao 266071, China; Cancer Institute, Qingdao University, Qingdao 266071, China.
| | - Qihui Zhou
- School of Rehabilitation Sciences and Engineering, University of Health and Rehabilitation Sciences, Qingdao 266071, China; Tianjin Enterprise Key Laboratory for Application Research of Hyaluronic Acid, Tianjin 300038, China; Zhejiang Engineering Research Center for Tissue Repair Materials, Wenzhou Institute, University of Chinese Academy of Sciences, Wenzhou, Zhejiang 325000, China.
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Malla R, Adem M, Chakraborty A. Complexity and diversity of FOXP3 isoforms: Novel insights into the regulation of the immune response in metastatic breast cancer. Int Immunopharmacol 2023; 118:110015. [PMID: 36931171 DOI: 10.1016/j.intimp.2023.110015] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/04/2023] [Accepted: 03/07/2023] [Indexed: 03/17/2023]
Abstract
FOXP3 is a key transcription factor in the regulation of immune responses, and recent studies have uncovered the complexity and diversity of FOXP3 isoforms in various cancers, including metastatic breast cancers (mBCs). It has dual role in the tumor microenvironment of mBCs. This review aims to provide novel insights into the complexity and diversity of FOXP3 isoforms in the regulation of the immune response in breast cancer. We discuss the molecular mechanisms underlying the function of FOXP3 isoforms, including their interaction with other proteins, regulation of gene expression, and impact on the immune system. We also highlight the importance of understanding the role of FOXP3 isoforms in breast cancer and the potential for using them as therapeutic targets. This review highlights the crucial role of FOXP3 isoforms in the regulation of the immune response in breast cancer and underscores the need for further research to fully comprehend their complex and diverse functions.
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Affiliation(s)
- RamaRao Malla
- Cancer Biology Laboratory, Department of Biochemistry and Bioinformatics, GITAM School of Science, GITAM (Deemed to be University), Visakhapatnam 530045, Andhra Pradesh, India.
| | - Meghapriya Adem
- Department of Biotechnology, Sri Padmavathi Mahila Visvavidhyalayam, Tirupati 517502, Andhra Pradesh, India
| | - Anindita Chakraborty
- Radiation Biology Laboratory, UGC-DAE-CSR, Kolkata Centere, Kolkata 700098, West Bengal, India
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Zhang L, Zhou C, Zhang S, Chen X, Liu J, Xu F, Liang W. Chemotherapy reinforces anti-tumor immune response and enhances clinical efficacy of immune checkpoint inhibitors. Front Oncol 2022; 12:939249. [PMID: 36003765 PMCID: PMC9393416 DOI: 10.3389/fonc.2022.939249] [Citation(s) in RCA: 15] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/08/2022] [Accepted: 07/04/2022] [Indexed: 12/03/2022] Open
Abstract
New evidence suggests that the clinical success of chemotherapy is not merely due to tumor cell toxicity but also arises from the restoration of immunosurveillance, which has been immensely neglected in previous preclinical and clinical researches. There is an urgent need for novel insights into molecular mechanisms and regimens that uplift the efficacy of immunotherapy since only a minority of cancer patients are responsive to immune checkpoint inhibitors (ICIs). Recent findings on combination therapy of chemotherapy and ICIs have shown promising results. This strategy increases tumor recognition and elimination by the host immune system while reducing immunosuppression by the tumor microenvironment. Currently, several preclinical studies are investigating molecular mechanisms that give rise to the immunomodulation by chemotherapeutic agents and exploit them in combination therapy with ICIs in order to achieve a synergistic clinical activity. In this review, we summarize studies that exhibit the capacity of conventional chemotherapeutics to elicit anti-tumor immune responses, thereby facilitating anti-tumor activities of the ICIs. In conclusion, combining chemotherapeutics with ICIs appears to be a promising approach for improving cancer treatment outcomes.
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Affiliation(s)
- Lin Zhang
- Department of Pharmacy, Shaoxing People’s Hospital, Shaoxing Hospital, Zhejiang University School of Medicine, Shaoxing, China
| | - Chao Zhou
- Department of Orthopedics, Zhoushan Guanghua Hospital, Zhoushan, China
| | - Songou Zhang
- College of Medicine, Shaoxing University, Shaoxing, China
| | - Xiaozhen Chen
- College of Medicine, Shaoxing University, Shaoxing, China
| | - Jian Liu
- Department of Hepatobiliary Surgery, Shanghai Oriental Hepatobiliary Hospital, Shanghai, China
| | - Fangming Xu
- Department of Gastroenterology, Zhoushan Hospital of Traditional Chinese Medicine Affiliated to Zhejiang Chinese Medical University, Zhoushan, China
| | - Wenqing Liang
- Medical Research Center, Zhoushan Hospital of Traditional Chinese Medicine Affiliated to Zhejiang Chinese Medical University, Zhoushan, China
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11
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Searching for Peptide Inhibitors of T Regulatory Cell Activity by Targeting Specific Domains of FOXP3 Transcription Factor. Biomedicines 2021; 9:biomedicines9020197. [PMID: 33671179 PMCID: PMC7922534 DOI: 10.3390/biomedicines9020197] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/23/2020] [Revised: 02/13/2021] [Accepted: 02/14/2021] [Indexed: 12/03/2022] Open
Abstract
(1) Background: The ability of cancer cells to evade the immune system is due in part to their capacity to induce and recruit T regulatory cells (Tregs) to the tumor microenvironment. Strategies proposed to improve antitumor immunity by depleting Tregs generally lack specificity and raise the possibility of autoimmunity. Therefore, we propose to control Tregs by their functional inactivation rather than depletion. Tregs are characterized by the expression of the Forkhead box protein 3 (FOXP3) transcription factor, which is considered their “master regulator”. Its interaction with DNA is assisted primarily by its interaction with other proteins in the so-called “Foxp3 interactome”, which elicits much of the characteristic Treg cell transcriptional signature. We speculated that the disruption of such a protein complex by using synthetic peptides able to bind Foxp3 might have an impact on the functionality of Treg cells and thus have a therapeutic potential in cancer treatment. (2) Methods: By using a phage-displayed peptide library, or short synthetic peptides encompassing Foxp3 fragments, or by studying the crystal structure of the Foxp3:NFAT complex, we have identified a series of peptides that are able to bind Foxp3 and inhibit Treg activity. (3) Results: We identified some peptides encompassing fragments of the leuzin zipper or the C terminal domain of Foxp3 with the capacity to inhibit Treg activity in vitro. The acetylation/amidation of linear peptides, head-to-tail cyclization, the incorporation of non-natural aminoacids, or the incorporation of cell-penetrating peptide motifs increased in some cases the Foxp3 binding capacity and Treg inhibitory activity of the identified peptides. Some of them have shown antitumoral activity in vivo. (4) Conclusions: Synthetic peptides constitute an alternative to inhibit Foxp3 protein–protein interactions intracellularly and impair Treg immunosuppressive activity. These peptides might be considered as potential hit compounds on the design of new immunotherapeutic approaches against cancer.
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12
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Morganti S, Curigliano G. Combinations using checkpoint blockade to overcome resistance. Ecancermedicalscience 2020; 14:1148. [PMID: 33574893 PMCID: PMC7864692 DOI: 10.3332/ecancer.2020.1148] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/07/2019] [Indexed: 12/11/2022] Open
Abstract
The advent of immunotherapy for cancer represented a paradigm shift in the treatment approach of neoplasia. Immune-checkpoint inhibitors (ICIs) were demonstrated to significantly improve outcomes, including overall survival across several cancer types, with yearly-durable responses. Nevertheless, many patients derive minor or no benefit with immune checkpoint (IC)-blockade, including patients with cancer types traditionally considered immunogenic. Combination strategies of ICIs with chemotherapy, radiotherapy, targeted therapies or other immunotherapy compounds have been conceived in order to boost the immune-responses and potentially overcome resistance to ICIs. This review focuses on mechanisms underlying resistance to IC-blockade and provides an overview of potential advantages and limitations of combination strategies currently under investigation.
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Affiliation(s)
- Stefania Morganti
- Division of Early Drug Development for Innovative Therapies, European Institute of Oncology (IEO), IRCCS, Via Ripamonti n.435, 20141, Milan, Italy
- Department of Oncology and Hemato-Oncology, University of Milan, Via Festa del Perdono n. 7, 20122 Milan, Italy
| | - Giuseppe Curigliano
- Division of Early Drug Development for Innovative Therapies, European Institute of Oncology (IEO), IRCCS, Via Ripamonti n.435, 20141, Milan, Italy
- Department of Oncology and Hemato-Oncology, University of Milan, Via Festa del Perdono n. 7, 20122 Milan, Italy
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Massa C, Karn T, Denkert C, Schneeweiss A, Hanusch C, Blohmer JU, Zahm DM, Jackisch C, van Mackelenbergh M, Thomalla J, Marme F, Huober J, Müller V, Schem C, Mueller A, Stickeler E, Biehl K, Fasching PA, Untch M, Loibl S, Weber K, Seliger B. Differential effect on different immune subsets of neoadjuvant chemotherapy in patients with TNBC. J Immunother Cancer 2020; 8:jitc-2020-001261. [PMID: 33199511 PMCID: PMC7670944 DOI: 10.1136/jitc-2020-001261] [Citation(s) in RCA: 20] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 10/09/2020] [Indexed: 01/03/2023] Open
Abstract
Background Triple-negative breast cancer (TNBC) is the most aggressive form of breast cancer (BC). Due to the absence of targets such as HER2 or hormone receptors, early TNBC is treated with surgery and chemotherapy. Since TNBC is also considered the most immunogenic type of BC with tumor infiltrating lymphocytes that are predictive for chemotherapy response and prognostic for patients′ survival, many different immunotherapeutic strategies are currently explored in clinical trials for the treatment of this disease. In order to efficiently combine chemotherapy with immunotherapy, it is important to evaluate the effect of chemotherapy on immune cells in vivo. Methods Peripheral blood was taken from 56 patients with TNBC undergoing neoadjuvant chemotherapy with nanoparticle albumin-bound paclitaxel (Nab-Pac) followed by epirubicin and cyclophosphamide (EC) at three different time points. Multicolor flow cytometry was used to characterize the immune cell composition and functional properties along neoadjuvant chemotherapy. Results Whereas the first phase of the neoadjuvant chemotherapy did not significantly alter the patients′ immune cell composition, after the second phase of chemotherapeutic administration most B cells (>90%) were lost and the frequency of natural killer (NK) cells and CD4+ T lymphocytes decreased approximately to 50%. In contrast, the frequency of CD8+ T cells were less affected. Conclusions Despite late consequences of Nab-Pac cannot be ruled out, these data suggest that different chemotherapeutics might have distinct effects on the immune cell repertoire and that different immune cell populations exhibit a specific susceptibility to these chemotherapies with B and NK cells being more affected than T cells. This might also have an impact on the combination of chemotherapies with immunotherapies. Trial registration number NCT02685059.
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Affiliation(s)
- Chiara Massa
- Insitute of Medical Immunology, Martin Luther University Halle Wittenberg, Halle, Sachsen-Anhalt, Germany
| | - Thomas Karn
- Department of Obstetrics and Gynecology, Goethe University Frankfurt, Frankfurt am Main, Hessen, Germany
| | - Carsten Denkert
- Institute of Pathology, Philipps-Universitat Marburg, Marburg, Hessen, Germany
| | - Andreas Schneeweiss
- Nationales Centrum für Tumorerkrankungen, Deutsches Krebsforschungszentrum, Heidelberg, Baden-Württemberg, Germany
| | | | - Jens-Uwe Blohmer
- Brustzentrum, Charite Universitatsmedizin Berlin, Berlin, Germany
| | | | - Christian Jackisch
- Department of Obstetrics and Gynecology, Sana Klinikum Offenbach GmbH, Offenbach, Hessen, Germany
| | - Marion van Mackelenbergh
- Department of Obstetrics and Gynecology, Universitätsklinikum Schleswig-Holstein, Kiel, Schleswig-Holstein, Germany
| | - Jörg Thomalla
- Praxis für Hämatologie und Onkologie Koblenz, Koblenz, Germany
| | - Frederik Marme
- Universitätsfrauenklinik, Universität Heidelberg, Heidelberg, Baden-Württemberg, Germany
| | - Jens Huober
- Universitätsklinikum Ulm, Ulm, Baden-Württemberg, Germany
| | - Volkmar Müller
- Department of Obstetrics and Gynecology, Universitätsklinikum Hamburg-Eppendorf, Hamburg, Hamburg, Germany
| | | | - Anja Mueller
- Insitute of Medical Immunology, Martin Luther University Halle Wittenberg, Halle, Sachsen-Anhalt, Germany
| | - Elmar Stickeler
- Department of Obstetrics and Gynecology, Uniklinik RWTH Aachen, Aachen, Nordrhein-Westfalen, Germany
| | - Katharina Biehl
- Insitute of Medical Immunology, Martin Luther University Halle Wittenberg, Halle, Sachsen-Anhalt, Germany
| | - Peter A Fasching
- Department of Gynecology and Obstetrics, Universitätsklinikum Erlangen, Erlangen, Bayern, Germany
| | - Michael Untch
- Department of Obstetrics and Gynecology, HELIOS Klinikum Berlin-Buch, Berlin, Germany
| | - Sibylle Loibl
- Department of Medicine and Research, German Breast Group, Neu-Isenburg, Hessen, Germany
| | - Karsten Weber
- Department of Medicine and Research, German Breast Group, Neu-Isenburg, Hessen, Germany
| | - Barbara Seliger
- Insitute of Medical Immunology, Martin Luther University Halle Wittenberg, Halle, Sachsen-Anhalt, Germany
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14
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Kopeček J, Yang J. Polymer nanomedicines. Adv Drug Deliv Rev 2020; 156:40-64. [PMID: 32735811 PMCID: PMC7736172 DOI: 10.1016/j.addr.2020.07.020] [Citation(s) in RCA: 58] [Impact Index Per Article: 11.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/17/2020] [Revised: 07/22/2020] [Accepted: 07/24/2020] [Indexed: 12/12/2022]
Abstract
Polymer nanomedicines (macromolecular therapeutics, polymer-drug conjugates, drug-free macromolecular therapeutics) are a group of biologically active compounds that are characterized by their large molecular weight. This review focuses on bioconjugates of water-soluble macromolecules with low molecular weight drugs and selected proteins. After analyzing the design principles, different structures of polymer carriers are discussed followed by the examination of the efficacy of the conjugates in animal models and challenges for their translation into the clinic. Two innovative directions in macromolecular therapeutics that depend on receptor crosslinking are highlighted: a) Combination chemotherapy of backbone degradable polymer-drug conjugates with immune checkpoint blockade by multivalent polymer peptide antagonists; and b) Drug-free macromolecular therapeutics, a new paradigm in drug delivery.
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Affiliation(s)
- Jindřich Kopeček
- Department of Pharmaceutics and Pharmaceutical Chemistry, University of Utah, Salt Lake City, UT 84112, USA; Department of Biomedical Engineering, University of Utah, Salt Lake City, UT 84112, USA.
| | - Jiyuan Yang
- Department of Pharmaceutics and Pharmaceutical Chemistry, University of Utah, Salt Lake City, UT 84112, USA
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15
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Heinhuis KM, Ros W, Kok M, Steeghs N, Beijnen JH, Schellens JHM. Enhancing antitumor response by combining immune checkpoint inhibitors with chemotherapy in solid tumors. Ann Oncol 2019; 30:219-235. [PMID: 30608567 DOI: 10.1093/annonc/mdy551] [Citation(s) in RCA: 378] [Impact Index Per Article: 63.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 08/08/2023] Open
Abstract
BACKGROUND Cancer immunotherapy has changed the standard of care for a subgroup of patients with advanced disease. Immune checkpoint blockade (ICB) in particular has shown improved survival compared with previous standards of care for several tumor types. Although proven to be successful in more immunogenic tumors, ICB is still largely ineffective in patients with tumors that are not infiltrated by immune cells, the so-called cold tumors. PATIENTS AND METHODS This review describes the effects of different chemotherapeutic agents on the immune system and the potential value of these different types of chemotherapy as combination partners with ICB in patients with solid tumors. Both preclinical data and currently ongoing clinical trials were evaluated. In addition, we reviewed findings regarding different dosing schedules, including the effects of an induction phase and applying metronomic doses of chemotherapy. RESULTS Combining ICB with other treatment modalities may lead to improved immunological conditions in the tumor microenvironment and could thereby enhance the antitumor immune response, even in tumor types that are so far unresponsive to ICB monotherapy. Chemotherapy, that was originally thought to be solely immunosuppressive, can exert immunomodulatory effects which may be beneficial in combination with immunotherapy. Each chemotherapeutic drug impacts the tumor microenvironment differently, and in order to determine the most suitable combination partners for ICB it is crucial to understand these mechanisms. CONCLUSION Preclinical studies demonstrate that the majority of chemotherapeutic drugs has been shown to exert immunostimulatory effects, either by inhibiting immunosuppressive cells and/or activating effector cells, or by increasing immunogenicity and increasing T-cell infiltration. However, for certain chemotherapeutic agents timing, dose and sequence of administration of chemotherapeutic agents and ICB is important. Further studies should focus on determining the optimal drug combinations, sequence effects and optimal concentration-time profiles in representative preclinical models.
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Affiliation(s)
- K M Heinhuis
- Divisions of Pharmacology, Utrecht University, Utrecht, The Netherlands
| | - W Ros
- Divisions of Pharmacology, Utrecht University, Utrecht, The Netherlands
| | - M Kok
- Medical Oncology and Molecular Oncology & Immunology, Utrecht University, Utrecht, The Netherlands
| | - N Steeghs
- Medical Oncology, Department of Clinical Pharmacology, Utrecht University, Utrecht, The Netherlands
| | - J H Beijnen
- Divisions of Pharmacology, Utrecht University, Utrecht, The Netherlands; Department of Pharmacy, The Netherlands Cancer Institute, Amsterdam, The Netherlands; MC Slotervaart, Amsterdam, The Netherlands; Utrecht Institute for Pharmaceutical Sciences, Utrecht University, Utrecht, The Netherlands
| | - J H M Schellens
- Utrecht Institute for Pharmaceutical Sciences, Utrecht University, Utrecht, The Netherlands.
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16
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Li J, Chen T, Yuan C, Zhao G, xu M, Li X, Cao J, Xing L. Effect of intravenous immunoglobulin on the function of Treg cells derived from immunosuppressed mice with Pseudomonas aeruginosa pneumonia. PLoS One 2017; 12:e0176843. [PMID: 28481908 PMCID: PMC5421750 DOI: 10.1371/journal.pone.0176843] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/16/2016] [Accepted: 04/18/2017] [Indexed: 12/31/2022] Open
Abstract
AIM The present study aimed to investigate the effect of intravenous immunoglobulin (IVIG) on regulatory T (Treg) cells derived from immunosuppressed mice with Pseudomonas aeruginosa (PA) pneumonia. METHODS A total of 108 BALB/c mice were randomly divided into the following groups: control group (Control), immunosuppressed group (IS), PA pneumonia group (PA), PA pneumonia in immunosuppressed group (IS + PA), PA pneumonia with IVIG treatment in immunocompetent group (PA + IVIG) and PA pneumonia with IVIG treatment in immunosuppressed group (IS + PA + IVIG). Each group comprised 18 mice. The combined PA pneumonia in immunosuppressed model and the treatment models were established. The mice in each group were sacrificed at 4, 8, and 24 h time points. The general condition and pathological changes in the lung tissues of the mice were monitored. Reverse transcription-polymerase chain reaction was used to detect the forkhead box P3 (FOXP3) mRNA relative expression level in the lung tissues. The enzyme-linked immunosorbent assay was used to detect the serum concentration of active transforming growth factor beta (TGF-β). RESULTS No inflammatory response were exhibited in the lung tissues of the mice in Control group and IS group, while varying degrees of acute lung injury were revealed in the mice in PA group, IS + PA group, PA + IVIG group and IS + PA + IVIG group. Lung tissue injury was most apparent at the 8 h time point, and it indicated the greatest effect in IS + PA group. Whereas tissue damages were alleviated in PA + IVIG group and IS + PA + IVIG group compared with IS + PA group. In addition, tissue damage lessened in PA + IVIG group compared with PA group and IS + PA + IVIG group. FOXP3 mRNA expression levels in the lung tissues and the serum concentration of TGF-β were lower in IS group, PA group, IS + PA group and IS + PA + IVIG group at the 4, 8 and 24 h time points, respectively compared with Control group. FOXP3 mRNA expression levels decreased in PA + IVIG group at the 4h time point and TGF-β serum concentrations decreased at the 4 and 8h time points compared with Control group, and subsequently increased. CONCLUSIONS In the immunosuppred model with PA pneumonia, the immune system was greatly compromised. IVIG partially restored the immunosuppressed functions of Treg cells, suppressed the overactivated immune system and ameliorated the development of the disease.
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Affiliation(s)
- Junlu Li
- Department of Respiratory Intensive Care Unit (RICU), The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, China
| | - Tingsang Chen
- Department of Respiratory Intensive Care Unit (RICU), The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, China
| | - Congcong Yuan
- Department of Respiratory Intensive Care Unit (RICU), The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, China
| | - Guoqiang Zhao
- School of basic medical sciences, Zhengzhou University, Zhengzhou, Henan, China
| | - Min xu
- Department of Laboratory, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, China
| | - Xiaoyan Li
- Department of Respiratory Intensive Care Unit (RICU), The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, China
| | - Jie Cao
- Department of Respiratory Intensive Care Unit (RICU), The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, China
| | - Lihua Xing
- Department of Respiratory Intensive Care Unit (RICU), The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, China
- * E-mail:
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Yang S, Kim CY, Hwang S, Kim E, Kim H, Shim H, Lee I. COEXPEDIA: exploring biomedical hypotheses via co-expressions associated with medical subject headings (MeSH). Nucleic Acids Res 2016; 45:D389-D396. [PMID: 27679477 PMCID: PMC5210615 DOI: 10.1093/nar/gkw868] [Citation(s) in RCA: 80] [Impact Index Per Article: 8.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/13/2016] [Revised: 09/20/2016] [Accepted: 09/21/2016] [Indexed: 12/21/2022] Open
Abstract
The use of high-throughput array and sequencing technologies has produced unprecedented amounts of gene expression data in central public depositories, including the Gene Expression Omnibus (GEO). The immense amount of expression data in GEO provides both vast research opportunities and data analysis challenges. Co-expression analysis of high-dimensional expression data has proven effective for the study of gene functions, and several co-expression databases have been developed. Here, we present a new co-expression database, COEXPEDIA (www.coexpedia.org), which is distinctive from other co-expression databases in three aspects: (i) it contains only co-functional co-expressions that passed a rigorous statistical assessment for functional association, (ii) the co-expressions were inferred from individual studies, each of which was designed to investigate gene functions with respect to a particular biomedical context such as a disease and (iii) the co-expressions are associated with medical subject headings (MeSH) that provide biomedical information for anatomical, disease, and chemical relevance. COEXPEDIA currently contains approximately eight million co-expressions inferred from 384 and 248 GEO series for humans and mice, respectively. We describe how these MeSH-associated co-expressions enable the identification of diseases and drugs previously unknown to be related to a gene or a gene group of interest.
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Affiliation(s)
- Sunmo Yang
- Department of Biotechnology, College of Life Science and Biotechnology, Yonsei University, Seoul, Korea
| | - Chan Yeong Kim
- Department of Biotechnology, College of Life Science and Biotechnology, Yonsei University, Seoul, Korea
| | - Sohyun Hwang
- Department of Biotechnology, College of Life Science and Biotechnology, Yonsei University, Seoul, Korea
| | - Eiru Kim
- Department of Biotechnology, College of Life Science and Biotechnology, Yonsei University, Seoul, Korea
| | - Hyojin Kim
- Department of Biotechnology, College of Life Science and Biotechnology, Yonsei University, Seoul, Korea
| | - Hongseok Shim
- Department of Biotechnology, College of Life Science and Biotechnology, Yonsei University, Seoul, Korea
| | - Insuk Lee
- Department of Biotechnology, College of Life Science and Biotechnology, Yonsei University, Seoul, Korea
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