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Agarwal D, Sharma G, Khadwal A, Toor D, Malhotra P. Advances in Vaccines, Checkpoint Blockade, and Chimeric Antigen Receptor-Based Cancer Immunotherapeutics. Crit Rev Immunol 2025; 45:65-80. [PMID: 39612278 DOI: 10.1615/critrevimmunol.2024053025] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/01/2024]
Abstract
Increase in cancer cases and research driven by understanding its causes, facilitated development of novel targeted immunotherapeutic strategies to overcome nonspecific cytotoxicity associated with conventional chemotherapy and radiotherapy. These target specific immunotherapeutic regimens have been evaluated for their efficacy, including: (1) vaccines harnessing tumor specific/associated antigens, (2) checkpoint blockade therapy using monoclonal antibodies against PD1, CTLA-4 and others, and (3) adoptive cell transfer approaches viz. chimeric antigen receptor (CAR)-cell-based therapies. Here, we review recent advancements on these target specific translational immunotherapeutic strategies against cancer/s and concerned limitations.
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Affiliation(s)
- Disha Agarwal
- Department of Translational & Regenerative Medicine, Postgraduate Institute of Medical Education & Research, Chandigarh, India
| | | | - Alka Khadwal
- Department of Clinical Hematology and Medical Oncology, Postgraduate Institute of Medical Education & Research, Chandigarh, India
| | - Devinder Toor
- Amity Institute of Virology and Immunology, Amity University Uttar Pradesh, Sector-125, Noida, 201313, Uttar Pradesh, India
| | - Pankaj Malhotra
- Department of Clinical Hematology and Medical Oncology, Postgraduate Institute of Medical Education & Research, Chandigarh, India
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Huang S, Tan C, Zheng J, Huang Z, Li Z, Lv Z, Chen W, Chen M, Yuan X, Chen C, Yan Q. Identification of RNMT as an immunotherapeutic and prognostic biomarker: From pan-cancer analysis to lung squamous cell carcinoma validation. Immunobiology 2024; 229:152836. [PMID: 39018675 DOI: 10.1016/j.imbio.2024.152836] [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: 04/05/2024] [Revised: 06/23/2024] [Accepted: 07/09/2024] [Indexed: 07/19/2024]
Abstract
BACKGROUND Dysregulation of RNA guanine-7 methyltransferase (RNMT) plays a crucial role in the tumor progression and immune responses. However, the detailed role of RNMT in pan-cancer is still unknown. METHODS Bulk transcriptomic data of pan-cancer were obtained from the Cancer Genome Atlas (TCGA), Genotype-Tissue Expression (GTEx), and Cancer Cell Line Encyclopedia (CCLE) databases. Single-cell transcriptomic and proteomics data of lung squamous cell carcinoma (LUSC) were analyzed in the Tumor Immune Single-cell Hub 2 (TISCH2) and Clinical Proteomic Tumor Analysis Consortium (CPTAC) databases, respectively. The correlation between RNMT expression and cancer prognosis was analyzed by Cox proportional hazards regression and Kaplan-Meier analyses. The correlation of RNMT expression with common immunoregulators, tumor mutation burden (TMB), microsatellite instability (MSI), mismatch repair (MMR), and DNA methyltransferase (DNMT) was analyzed. Additionally, the correlation between RNMT expression and immune infiltration level was evaluated. A total of 1287 machine learning combinations were used to construct prognostic models for LUSC. qRT-PCR and Western blot were used to validate the bioinformatics findings of RNMT upregulation in LUSC. RESULTS RNMT was widely expressed across different cancers, with significant correlation to prognosis in cancers such as kidney chromophobe (KICH) (p = 0.0033, HR = 7.12), liver hepatocellular carcinoma (LIHC) (p = 0.01, HR = 1.41), and others. Notably, RNMT participates in the regulation of the tumor microenvironment. RNMT expression positively correlated with immune cell expression (Spearman's rank correlation, p < 0.05). Moreover, RNMT expression was strongly associated with immunoregulators, TMB, MSI, MMR, and DNMT in most cancer types. Notably, RNMT expression displayed excellent prognostic and immunological performance in LUSC. The expression of RNMT was mainly enriched in B cells of LUSC tissues. qRT-PCR and Western blot verified the high expression of RNMT in LUSC. CONCLUSION RNMT expression widely correlated with prognosis and immune infiltration in various tumors, especially LUSC. The RNMT detection may provide a new idea for future tumor immune studies and treatment strategies.
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Affiliation(s)
- Shuqiang Huang
- Center for Reproductive Medicine, the Affiliated Qingyuan Hospital (Qingyuan People's Hospital), Guangzhou Medical University, Qingyuan, Guangdong 511518, China
| | - Cuiyu Tan
- Center for Reproductive Medicine, the Affiliated Qingyuan Hospital (Qingyuan People's Hospital), Guangzhou Medical University, Qingyuan, Guangdong 511518, China
| | - Jinzhen Zheng
- Center for Reproductive Medicine, the Affiliated Qingyuan Hospital (Qingyuan People's Hospital), Guangzhou Medical University, Qingyuan, Guangdong 511518, China
| | - Zhugu Huang
- School of Pediatrics, Guangzhou Medical University, Guangzhou, Guangdong 511436, China
| | - Zhihong Li
- Center for Reproductive Medicine, the Affiliated Qingyuan Hospital (Qingyuan People's Hospital), Guangzhou Medical University, Qingyuan, Guangdong 511518, China
| | - Ziyin Lv
- The First School of Clinical Medicine, Guangzhou Medical University, Guangzhou, Guangdong 511436, China
| | - Wanru Chen
- The Third School of Clinical Medicine, Guangzhou Medical University, Guangzhou, Guangdong 511436, China
| | - Miaoqi Chen
- Center for Reproductive Medicine, the Affiliated Qingyuan Hospital (Qingyuan People's Hospital), Guangzhou Medical University, Qingyuan, Guangdong 511518, China
| | - Xiaojun Yuan
- Center for Reproductive Medicine, the Affiliated Qingyuan Hospital (Qingyuan People's Hospital), Guangzhou Medical University, Qingyuan, Guangdong 511518, China
| | - Cairong Chen
- Center for Reproductive Medicine, the Affiliated Qingyuan Hospital (Qingyuan People's Hospital), Guangzhou Medical University, Qingyuan, Guangdong 511518, China; Guangdong Engineering Technology Research Center of Urinary Continence and Reproductive Medicine, the Affiliated Qingyuan Hospital (Qingyuan People's Hospital), Guangzhou Medical University, Qingyuan, Guangdong 511518, China.
| | - Qiuxia Yan
- Center for Reproductive Medicine, the Affiliated Qingyuan Hospital (Qingyuan People's Hospital), Guangzhou Medical University, Qingyuan, Guangdong 511518, China; Guangdong Engineering Technology Research Center of Urinary Continence and Reproductive Medicine, the Affiliated Qingyuan Hospital (Qingyuan People's Hospital), Guangzhou Medical University, Qingyuan, Guangdong 511518, China.
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Rastin F, Javid H, Oryani MA, Rezagholinejad N, Afshari AR, Karimi-Shahri M. Immunotherapy for colorectal cancer: Rational strategies and novel therapeutic progress. Int Immunopharmacol 2024; 126:111055. [PMID: 37992445 DOI: 10.1016/j.intimp.2023.111055] [Citation(s) in RCA: 31] [Impact Index Per Article: 31.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/27/2023] [Revised: 09/30/2023] [Accepted: 10/09/2023] [Indexed: 11/24/2023]
Abstract
There are increasing incidences and mortality rates for colorectal cancer in the world. It is common for chemotherapy and radiation given to patients with colorectal cancer to cause toxicities that limit their effectiveness and cause cancer cells to become resistant to these treatments. Additional targeted treatments are needed to improve patient's quality of life and outcomes. Immunotherapy has rapidly emerged as an incredibly exciting and promising avenue for cancer treatment in recent years. This innovative approach provides novel options for tackling solid tumors, effectively establishing itself as a new cornerstone in cancer treatment. Specifically, in the realm of colorectal cancer (CRC), there is great promise in developing new drugs that target immune checkpoints, offering a hopeful and potentially transformative solution. While immunotherapy of CRC has made significant advances, there are still obstacles and limitations. CRC patients have a poor response to treatment because of the immune-suppressing function of their tumor microenvironment (TME). In addition to blocking inhibitory immune checkpoints, checkpoint-blocking antibodies may also boost immune responses against tumors. The review summarizes recent advances in immune checkpoint inhibitors (ICIs) for CRC, including CTLA-4, PD-1, PD-L1, LAG-3, and TIM-3.
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Affiliation(s)
- Farangis Rastin
- Department of Biology, Faculty of Science, Ferdowsi University of Mashhad, Mashhad, Iran
| | - Hossein Javid
- Department of Medical Laboratory Sciences, Varastegan Institute for Medical Sciences, Mashhad, Iran; Department of Clinical Biochemistry, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran; Surgical Oncology Research Center, Mashhad University of Medical Sciences, Mashhad, Iran.
| | - Mahsa Akbari Oryani
- Department of Pathology, School of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
| | | | - Amir-R Afshari
- Department of Physiology and Pharmacology, School of Medicine, North Khorasan University of Medical Sciences, Bojnurd, Iran
| | - Mehdi Karimi-Shahri
- Department of Pathology, School of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran; Department of Pathology, School of Medicine, Gonabad University of Medical Sciences, Gonabad, Iran.
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Wang S, Guo Q, Xu R, Lin P, Deng G, Xia X. Combination of ferroptosis and pyroptosis dual induction by triptolide nano-MOFs for immunotherapy of Melanoma. J Nanobiotechnology 2023; 21:383. [PMID: 37858186 PMCID: PMC10585872 DOI: 10.1186/s12951-023-02146-0] [Citation(s) in RCA: 21] [Impact Index Per Article: 10.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/26/2023] [Accepted: 10/09/2023] [Indexed: 10/21/2023] Open
Abstract
Immunotherapy has good potential to eradicate tumors in the long term. However, due to the low immunogenicity of tumor cells, current cancer immunotherapies are not effective. To address this limitation, we constructed a BSA-FA functionalized iron-containing metal-organic framework (TPL@TFBF) that triggers a potent systemic anti-tumor immune response by inducing ferroptosis and pyroptosis in tumor cells and releasing large quantities of damage-associated molecular patterns (DAMPs) to induce immunogenicity, and showing excellent efficacy against melanoma lung metastases in vivo. This nanoplatform forms a metal-organic framework through the coordination between tannic acid (TA) and Fe3+ and is then loaded with triptolide (TPL), which is coated with FA-modified BSA. The nanoparticles target melanoma cells by FA modification, releasing TPL, Fe3+ and TA. Fe3+ is reduced to Fe2+ by TA, triggering the Fenton reaction and resulting in ROS production. Moreover, TPL increases the production of intracellular ROS by inhibiting the expression of nuclear factor erythroid-2 related factor (Nrf2). Such simultaneous amplification of intracellular ROS induces the cells to undergo ferroptosis and pyroptosis, releasing large amounts of DAMPs, which stimulate antigen presentation of dendritic cells (DCs) and the proliferation of cytotoxic T lymphocytes (CD4+/CD8 + T cells) to inhibit tumor and lung metastasis. In addition, combining nanoparticle treatment with immune checkpoint blockade (ICB) further inhibits melanoma growth. This work provides a new strategy for tumor immunotherapy based on various combinations of cell death mechanisms.
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Affiliation(s)
- Shengmei Wang
- School of Pharmacy, Hunan University of Chinese Medicine, Changsha, 410208, Hunan, China
| | - Qiuyan Guo
- School of Pharmacy, Hunan University of Chinese Medicine, Changsha, 410208, Hunan, China
| | - Rubing Xu
- School of Pharmacy, Hunan University of Chinese Medicine, Changsha, 410208, Hunan, China
| | - Peng Lin
- School of Pharmacy, Hunan University of Chinese Medicine, Changsha, 410208, Hunan, China
| | - Guoyan Deng
- The First Hospital of Hunan University of Chinese Medicine, Changsha, 410007, Hunan, China
| | - Xinhua Xia
- School of Pharmacy, Hunan University of Chinese Medicine, Changsha, 410208, Hunan, China.
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Meng Q, Ding B, Ma P, Lin J. Interrelation between Programmed Cell Death and Immunogenic Cell Death: Take Antitumor Nanodrug as an Example. SMALL METHODS 2023; 7:e2201406. [PMID: 36707416 DOI: 10.1002/smtd.202201406] [Citation(s) in RCA: 40] [Impact Index Per Article: 20.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 10/28/2022] [Revised: 12/20/2022] [Indexed: 05/17/2023]
Abstract
Programmed cell death (PCD, mainly including apoptosis, necrosis, ferroptosis, pyroptosis, and autophagy) and immunogenic cell death (ICD), as important cell death mechanisms, are widely reported in cancer therapy, and understanding the relationship between the two is significant for clinical tumor treatments. Considering that vast nanodrugs are developed to induce tumor PCD and ICD simultaneously, in this review, the interrelationship between PCD and ICD is described using nanomedicines as examples. First, an overview of PCD patterns and focus on the morphological differences and interconnections among them are provided. Then the interrelationship between apoptosis and ICD in terms of endoplasmic reticulum stress is described by introducing various cancer treatments and the recent developments of nanomedicines with inducible immunogenicity. Next, the crosstalk between non-apoptotic (including necrosis, ferroptosis, pyroptosis, and autophagy) signaling pathways and ICD is introduced and their relationship through various nanomedicines as examples is further illustrated. Finally, the relationship between PCD and ICD and its application prospects in the development of new ICD nanomaterials are summarized. This review is believed to deepen the understanding of the relationship between PCD and ICD, extend the biomedical applications of various nanodrugs, and promote the progress of clinical tumor therapy.
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Affiliation(s)
- Qi Meng
- State Key Laboratory of Rare Earth Resource Utilization, Changchun Institute of Applied Chemistry, Chinese Academy of Sciences, Changchun, 130022, China
- School of Applied Chemistry and Engineering, University of Science and Technology of China, Hefei, 230026, China
| | - Binbin Ding
- State Key Laboratory of Rare Earth Resource Utilization, Changchun Institute of Applied Chemistry, Chinese Academy of Sciences, Changchun, 130022, China
| | - Ping'an Ma
- State Key Laboratory of Rare Earth Resource Utilization, Changchun Institute of Applied Chemistry, Chinese Academy of Sciences, Changchun, 130022, China
- School of Applied Chemistry and Engineering, University of Science and Technology of China, Hefei, 230026, China
| | - Jun Lin
- State Key Laboratory of Rare Earth Resource Utilization, Changchun Institute of Applied Chemistry, Chinese Academy of Sciences, Changchun, 130022, China
- School of Applied Chemistry and Engineering, University of Science and Technology of China, Hefei, 230026, China
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Kumar A, Gautam V, Sandhu A, Rawat K, Sharma A, Saha L. Current and emerging therapeutic approaches for colorectal cancer: A comprehensive review. World J Gastrointest Surg 2023; 15:495-519. [PMID: 37206081 PMCID: PMC10190721 DOI: 10.4240/wjgs.v15.i4.495] [Citation(s) in RCA: 80] [Impact Index Per Article: 40.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/21/2022] [Revised: 01/11/2023] [Accepted: 03/03/2023] [Indexed: 04/22/2023] Open
Abstract
Colorectal cancer (CRC) affects 1 in 23 males and 1 in 25 females, making it the third most common cancer. With roughly 608000 deaths worldwide, CRC accounts for 8% of all cancer-related deaths, making it the second most common cause of death due to cancer. Standard and conventional CRC treatments include surgical expurgation for resectable CRC and radiotherapy, chemotherapy, immunotherapy, and their combinational regimen for non-resectable CRC. Despite these tactics, nearly half of patients develop incurable recurring CRC. Cancer cells resist the effects of chemotherapeutic drugs in a variety of ways, including drug inactivation, drug influx and efflux modifications, and ATP-binding cassette transporter overexpression. These constraints necessitate the development of new target-specific therapeutic strategies. Emerging therapeutic approaches, such as targeted immune boosting therapies, non-coding RNA-based therapies, probiotics, natural products, oncolytic viral therapies, and biomarker-driven therapies, have shown promising results in preclinical and clinical studies. We tethered the entire evolutionary trends in the development of CRC treatments in this review and discussed the potential of new therapies and how they might be used in conjunction with conventional treatments as well as their advantages and drawbacks as future medicines.
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Affiliation(s)
- Anil Kumar
- Department of Pharmacology, Post Graduate Institute of Medical Education and Research, Chandigarh 160012, India
| | - Vipasha Gautam
- Department of Pharmacology, Post Graduate Institute of Medical Education and Research, Chandigarh 160012, India
| | - Arushi Sandhu
- Department of Pharmacology, Post Graduate Institute of Medical Education and Research, Chandigarh 160012, India
| | - Kajal Rawat
- Department of Pharmacology, Post Graduate Institute of Medical Education and Research, Chandigarh 160012, India
| | - Antika Sharma
- Department of Pharmacology, Post Graduate Institute of Medical Education and Research, Chandigarh 160012, India
| | - Lekha Saha
- Department of Pharmacology, Post Graduate Institute of Medical Education and Research, Chandigarh 160012, India
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Ye K, Wang K, Wang T, Tang H, Wang L, Zhang W, Jiang S, Zhang X, Zhang K. Design, synthesis, biological evaluation of urea substituted 1,2,5-oxadiazole-3-carboximidamides as novel indoleamine 2,3-dioxygenase-1 (IDO1) inhibitors. Eur J Med Chem 2023; 250:115217. [PMID: 36842272 DOI: 10.1016/j.ejmech.2023.115217] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/17/2023] [Revised: 02/10/2023] [Accepted: 02/18/2023] [Indexed: 02/22/2023]
Abstract
Indoleamine 2,3-dioxygenase-1 (IDO1) has been considered as an attractive target for oncology immunotherapy due to its immunosuppressive effects on the tumor microenvironment. The most advanced IDO1 inhibitor epacadostat in combination with anti-PD-1 antibody failed to show desirable objective response. Epacadostat is now reevaluated in phase III clinical trials, but its pharmacokinetic (PK) properties are unsatisfactory. To further unravel the antitumor efficacy of IDO1 inhibitors, we designed a series of epacadostat analogues by introducing various urea-containing side chains. In particular, the most active compound 3 showed superior inhibitory potency against recombinant hIDO1 and hIDO1 in HeLa cells induced by interferon γ (IFNγ) relative to epacadostat (3, biochemical hIDO1 IC50 = 67.4 nM, HeLa hIDO1 IC50 = 17.6 nM; epacadostat, biochemical hIDO1 IC50 = 75.9 nM, HeLa hIDO1 IC50 = 20.6 nM). Moreover, compound 3 exhibited improved physicochemical properties and rat PK profile with better oral exposure and bioavailability compared with epacadostat. Importantly, this compound exhibited comparable antitumor efficacy with epacadostat in LLC syngeneic xenograft models. Hence, compound 3 represents a promising lead compound for discovery of more effective IDO1 inhibitors.
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Affiliation(s)
- Ke Ye
- Department of Medicinal Chemistry, School of Pharmacy, China Pharmaceutical University, Nanjing, 210009, China
| | - Kaizheng Wang
- Department of Medicinal Chemistry, School of Pharmacy, China Pharmaceutical University, Nanjing, 210009, China
| | - Tianyu Wang
- Department of Medicinal Chemistry, School of Pharmacy, China Pharmaceutical University, Nanjing, 210009, China
| | - He Tang
- Department of Medicinal Chemistry, School of Pharmacy, China Pharmaceutical University, Nanjing, 210009, China
| | - Lin Wang
- Department of Medicinal Chemistry, School of Pharmacy, China Pharmaceutical University, Nanjing, 210009, China
| | - Wanheng Zhang
- Department of Medicinal Chemistry, School of Pharmacy, China Pharmaceutical University, Nanjing, 210009, China
| | - Sheng Jiang
- Department of Medicinal Chemistry, School of Pharmacy, China Pharmaceutical University, Nanjing, 210009, China.
| | - Xiangyu Zhang
- Department of Medicinal Chemistry, School of Pharmacy, China Pharmaceutical University, Nanjing, 210009, China.
| | - Kuojun Zhang
- Department of Medicinal Chemistry, School of Pharmacy, China Pharmaceutical University, Nanjing, 210009, China.
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8
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Soluble Programmed Death-Ligand 1 (sPD-L1) is Elevated in Aggressive Prostate Cancer Disease Among African Men. Oncol Ther 2022; 10:185-193. [PMID: 35128628 PMCID: PMC9098749 DOI: 10.1007/s40487-022-00184-6] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/10/2021] [Accepted: 01/13/2022] [Indexed: 01/22/2023] Open
Abstract
Introduction Programmed death 1 (PD-1)/programmed death-ligand 1 (PD-L1)-targeted immunotherapies have become a new mode of treatment for several tumours; however, there is limited evidence on the expression and prognostic value of PD-1/PD-L1 in prostate cancer, especially in African men. Methods Plasma concentrations of PD-L1/PD-1 were assessed using enzyme-linked immunosorbent assay in patients with prostate cancer and normal healthy controls at the Uganda Cancer Institute. The associations between plasma PD-L1/PD-1 concentration levels and serum prostate-specific antigen (PSA) levels, Gleason scores, age, and body mass index (BMI) were determined. Results We found significant differences in the median plasma concentrations of PD-L1 and PD-1 immune checkpoint molecules between prostate cancer cases and normal healthy controls of 0.285 vs 0.035 (p = 0.001) and 0.596 vs 0.355 (p = 0.017), respectively. We found no significant association between age, serum PSA levels, BMI and Gleason scores, and PD-1 among patients with prostate cancer and controls. However, elevated levels of PD-L1 were significantly associated with higher Gleason scores among patients with prostate cancer (p = 0.014). Conclusions Elevated PD-L1 levels were statistically significantly linked to high Gleason scores. These results may guide clinicians in assessing the prognosis of patients individually and selecting patients who will be suitable candidates for anti-PD-L1 immunotherapy. Supplementary Information The online version contains supplementary material available at 10.1007/s40487-022-00184-6.
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Nanobodies Enhancing Cancer Visualization, Diagnosis and Therapeutics. Int J Mol Sci 2021; 22:ijms22189778. [PMID: 34575943 PMCID: PMC8472690 DOI: 10.3390/ijms22189778] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/28/2021] [Revised: 08/30/2021] [Accepted: 09/05/2021] [Indexed: 01/21/2023] Open
Abstract
Worldwide, cancer is a serious health concern due to the increasing rates of incidence and mortality. Conventional cancer imaging, diagnosis and treatment practices continue to substantially contribute to the fight against cancer. However, these practices do have some risks, adverse effects and limitations, which can affect patient outcomes. Although antibodies have been developed, successfully used and proven beneficial in various oncology practices, the use of antibodies also comes with certain challenges and limitations (large in size, poor tumor penetration, high immunogenicity and a long half-life). Therefore, it is vital to develop new ways to visualize, diagnose and treat cancer. Nanobodies are novel antigen-binding fragments that possess many advantageous properties (small in size, low immunogenicity and a short half-life). Thus, the use of nanobodies in cancer practices may overcome the challenges experienced with using traditional antibodies. In this review, we discuss (1) the challenges with antibody usage and the superior qualities of nanobodies; (2) the use of antibodies and nanobodies in cancer imaging, diagnosis, drug delivery and therapy (surgery, radiotherapy, chemotherapy and immunotherapy); and (3) the potential improvements in oncology practices due to the use of nanobodies as compared to antibodies.
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10
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Liu Q. World-First Phase I Clinical Trial for CRISPR-Cas9 PD-1-Edited T-Cells in Advanced Nonsmall Cell Lung Cancer. Glob Med Genet 2020; 7:73-74. [PMID: 33392608 PMCID: PMC7772009 DOI: 10.1055/s-0040-1721451] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2022] Open
Affiliation(s)
- Qian Liu
- Tianjin Lung Cancer Institute, Tianjin Medical University General Hospital, Tianjin, China
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11
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Johdi NA, Sukor NF. Colorectal Cancer Immunotherapy: Options and Strategies. Front Immunol 2020; 11:1624. [PMID: 33042104 PMCID: PMC7530194 DOI: 10.3389/fimmu.2020.01624] [Citation(s) in RCA: 286] [Impact Index Per Article: 57.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/10/2020] [Accepted: 06/17/2020] [Indexed: 12/24/2022] Open
Abstract
Colorectal cancer is the third most common cancer in the world with increasing incidence and mortality rates globally. Standard treatments for colorectal cancer have always been surgery, chemotherapy and radiotherapy which may be used in combination to treat patients. However, these treatments have many side effects due to their non-specificity and cytotoxicity toward any cells including normal cells that are growing and dividing. Furthermore, many patients succumb to relapse even after a series of treatments. Thus, it is crucial to have more alternative and effective treatments to treat CRC patients. Immunotherapy is one of the new alternatives in cancer treatment. The strategy is to utilize patients' own immune systems in combating the cancer cells. Cancer immunotherapy overcomes the issue of specificity which is the major problem in chemotherapy and radiotherapy. The normal cells with no cancer antigens are not affected. The outcomes of some cancer immunotherapy have been astonishing in some cases, but some which rely on the status of patients' own immune systems are not. Those patients who responded well to cancer immunotherapy have a better prognostic and better quality of life.
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Affiliation(s)
- Nor Adzimah Johdi
- UKM Medical Molecular Biology Institute (UMBI), National University of Malaysia, Bangi, Malaysia
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Abakushina EV, Gelm YV, Pasova IA, Bazhin AV. Immunotherapeutic Approaches for the Treatment of Colorectal Cancer. BIOCHEMISTRY (MOSCOW) 2019; 84:720-728. [PMID: 31509724 DOI: 10.1134/s0006297919070046] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
Colorectal cancer (CRC) originating from the cells of the colon or rectum has a high mortality rate worldwide. Numerous attempts have been made to raise the overall survival rates of CRC patients. It is well-known that the development of malignant neoplasms is accompanied by suppression of the immune system, which is likely the cause for the failure of standard treatment methods. Immune response has long been an issue of great interest in cancer therapy and anti-tumor immunity that consider the development of immunotherapeutic antitumor methods resulting in the immune system activation as an important issue. This review discusses main immunotherapeutic approaches available for the CRC treatment.
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Affiliation(s)
- E V Abakushina
- Tsyb Medical Radiological Research Center, Branch of the National Medical Research Radiological Center, Ministry of Health of the Russian Federation, Obninsk, Kaluga Region, 249036, Russia.
| | - Yu V Gelm
- Tsyb Medical Radiological Research Center, Branch of the National Medical Research Radiological Center, Ministry of Health of the Russian Federation, Obninsk, Kaluga Region, 249036, Russia
| | - I A Pasova
- Tsyb Medical Radiological Research Center, Branch of the National Medical Research Radiological Center, Ministry of Health of the Russian Federation, Obninsk, Kaluga Region, 249036, Russia
| | - A V Bazhin
- Ludwig-Maximilians-University Munich, Department of General, Visceral, Transplant, Vascular and Thoracic Surgery, Munich, 81377, Germany.
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Norwood TG, Wang MJ, Huh WK. Combination checkpoint inhibitor therapy induces multiple immune major related adverse events in the treatment of vaginal melanoma: A cautionary case report. Gynecol Oncol Rep 2019; 30:100508. [PMID: 31737773 PMCID: PMC6849148 DOI: 10.1016/j.gore.2019.100508] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/02/2019] [Revised: 10/03/2019] [Accepted: 10/07/2019] [Indexed: 12/17/2022] Open
Abstract
As more ICIs are approved, better education is needed for patients and providers. Major irAEs, signs of worsening immune toxicity, can present with benign symptoms. IrAEs should be considered when patients on ICIs present with new symptoms. Patients on ICIs may present to a variety of healthcare settings with irAEs. Providers should be educated on basic work-up and treatment options for irAEs. Background Immune checkpoint inhibitors (ICI) eliminate cancer cells through release of inhibition of cytotoxic CD8+ lymphocytes. Potent systemic activation of immune cells provides unprecedented efficacy in some types of advanced cancer therapy, but also often induces serious immune related adverse events (irAEs) that can be devastating if not promptly identified and properly managed. Herein, we describe the case of multiple major irAEs manifesting after administration of combination ICI therapy in a patient with vaginal melanoma. Case: A 54-year-old, G2P0 woman with recurrent metastatic vaginal melanoma, following three doses of combination nivolumab-ipilimumab immunotherapy, presented for admission at our tertiary care center for the work-up of sudden-onset of colitis of unknown etiology. Prior to admission at our facility, the patient was diagnosed with a severe maculopapular rash, headaches and hyponatremia in the weeks immediately following initiation of therapy. During work up of the colitis, infectious etiologies were ruled out, and the patient was discharged on a steroid taper for treatment of presumed immune-related colitis. Consideration of salt-supplement resistant hyponatremia with new onset frontal headache in the setting of immune-related colitis indicated possible hypophysitis. With high suspicion for multiple high grade irAEs, ICI was discontinued, and the patient was given high dose intravenous steroids prior to discharge with a prednisone dose taper for outpatient management. After control of irAEs was achieved, ipilimumab therapy was subsequently discontinued to minimize the chance of recurrent irAEs, yet nivolumab monotherapy was resumed in an attempt to control disease progression that could occur in with iatrogenic immunosuppression. Conclusion ICIs have demonstrated the ability to induce improved long-term survival in metastatic cutaneous or mucosal melanomas, including those of gynecologic origin. As ICI therapy becomes more widespread, healthcare providers across all fields of medicine need be vigilant to recognize the symptoms of irAEs that can often masquerade as common illnesses to prevent potentially dangerous irreversible immune toxicities.
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Affiliation(s)
- T Graham Norwood
- University of Alabama at Birmingham, School of Medicine. Birmingham, AL, United States
| | - Michelle J Wang
- University of Alabama at Birmingham, School of Medicine. Birmingham, AL, United States
| | - Warner K Huh
- University of Alabama at Birmingham, Department of Obstetrics and Gynecology, Birmingham, Division of Gynecology Oncology. Birmingham, AL, United States
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Ohadian Moghadam S, Nowroozi MR. Toll‐like receptors: The role in bladder cancer development, progression and immunotherapy. Scand J Immunol 2019; 90:e12818. [DOI: 10.1111/sji.12818] [Citation(s) in RCA: 31] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/11/2019] [Revised: 08/16/2019] [Accepted: 08/20/2019] [Indexed: 12/18/2022]
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15
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Grywalska E, Smarz-Widelska I, Mertowski S, Gosik K, Mielnik M, Podgajna M, Abramiuk M, Drop B, Roliński J, Załuska W. CTLA-4 Expression Inversely Correlates with Kidney Function and Serum Immunoglobulin Concentration in Patients with Primary Glomerulonephritides. Arch Immunol Ther Exp (Warsz) 2019; 67:335-349. [PMID: 31177287 PMCID: PMC6732130 DOI: 10.1007/s00005-019-00548-3] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/06/2019] [Accepted: 05/21/2019] [Indexed: 12/01/2022]
Abstract
Major causes of chronic kidney disease are primary proliferative and nonproliferative glomerulonephritides (PGN and NPGN). However, the pathogenesis of PGN and NPGN is still not fully understood. Cytotoxic T-lymphocyte-associated antigen-4 (CTLA-4) is a T-cell membrane receptor that plays a key role in T-cell inhibition. Despite its role in autoimmunological diseases, little is known about the involvement of CTLA-4 in the pathogenesis of PGN and NPGN. The objective of this study was to determine the role of CTLA-4 in the pathogenesis of PGN and NPGN by evaluating the frequencies of T and B lymphocytes expressing CTLA-4 and the serum concentration of the sCTLA-4 isoform in patients with PGN and NPGN in relation to clinical parameters. The study included peripheral blood (PB) samples from 40 PGN and NPGN patients and 20 healthy age- and sex-matched volunteers (control group). The viable PB lymphocytes were labeled with fluorochrome-conjugated monoclonal anti-CTLA-4 antibodies and analyzed using flow cytometry. The serum concentration of sCTLA-4 was measured using ELISA. The frequencies and absolute counts of CD4+/CTLA-4+ T lymphocytes, CD8+/CTLA-4+ T lymphocytes and CD19+/CTLA-4+ B lymphocytes and the serum sCTLA-4 concentration were lower in PGN and NPGN patients that in the control group. Reduced sCTLA-4 expression was associated with a lower concentration of serum immunoglobulins. Our results indicate that deregulation of CTLA-4 expression may result in continuous activation of T cells and contribute to the pathogenesis of PGN and NPGN.
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Affiliation(s)
- Ewelina Grywalska
- Department of Clinical Immunology and Immunotherapy, Medical University of Lublin, Chodzki 4a, 20-093, Lublin, Poland.
| | - Iwona Smarz-Widelska
- Department of Nephrology, Cardinal Stefan Wyszynski Provincial Hospital in Lublin, Lublin, Poland
| | - Sebastian Mertowski
- Department of Clinical Immunology and Immunotherapy, Medical University of Lublin, Chodzki 4a, 20-093, Lublin, Poland
| | - Krzysztof Gosik
- Department of Clinical Immunology and Immunotherapy, Medical University of Lublin, Chodzki 4a, 20-093, Lublin, Poland
| | - Michał Mielnik
- Department of Hematooncology and Bone Marrow Transplantation, Medical University of Lublin, Lublin, Poland
| | - Martyna Podgajna
- Department of Clinical Immunology and Immunotherapy, Medical University of Lublin, Chodzki 4a, 20-093, Lublin, Poland
| | - Monika Abramiuk
- The First Department of Gynecologic Oncology and Gynecology, Medical University of Lublin, Lublin, Poland
| | - Bartłomiej Drop
- Department of Informatics and Medical Statistics, Medical University of Lublin, Lublin, Poland
| | - Jacek Roliński
- Department of Clinical Immunology and Immunotherapy, Medical University of Lublin, Chodzki 4a, 20-093, Lublin, Poland
| | - Wojciech Załuska
- Department of Nephrology, Medical University of Lublin, Lublin, Poland
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Anwar MA, El-Baba C, Elnaggar MH, Elkholy YO, Mottawea M, Johar D, Al Shehabi TS, Kobeissy F, Moussalem C, Massaad E, Omeis I, Darwiche N, Eid AH. Novel therapeutic strategies for spinal osteosarcomas. Semin Cancer Biol 2019; 64:83-92. [PMID: 31152785 DOI: 10.1016/j.semcancer.2019.05.018] [Citation(s) in RCA: 36] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/15/2019] [Revised: 05/28/2019] [Accepted: 05/28/2019] [Indexed: 12/24/2022]
Abstract
At the dawn of the third millennium, cancer has become the bane of twenty-first century man, and remains a predominant public health burden, affecting welfare and life expectancy globally. Spinal osteogenic sarcoma, a primary spinal malignant tumor, is a rare and challenging neoplastic disease to treat. After the conventional therapeutic modalities of chemotherapy, radiation and surgery have been exhausted, there is currently no available alternative therapy in managing cases of spinal osteosarcoma. The defining signatures of tumor survival are characterised by cancer cell ability to stonewall immunogenic attrition and apoptosis by various means. Some of these biomarkers, namely immune-checkpoints, have recently been exploited as druggable targets in osteosarcoma and many other different cancers. These promising strides made by the use of reinvigorated immunotherapeutic approaches may lead to significant reduction in spinal osteosarcoma disease burden and corresponding reciprocity in increase of survival rates. In this review, we provide the background to spinal osteosarcoma, and proceed to elaborate on contribution of the complex ecology within tumor microenvironment giving arise to cancerous immune escape, which is currently receiving considerable attention. We follow this section on the tumor microenvironment by a brief history of cancer immunity. Also, we draw on the current knowledge of treatment gained from incidences of osteosarcoma at other locations of the skeleton (long bones of the extremities in close proximity to the metaphyseal growth plates) to make a case for application of immunity-based tools, such as immune-checkpoint inhibitors and vaccines, and draw attention to adverse upshots of immune-checkpoint blockers as well. Finally, we describe the novel biotechnique of CRISPR/Cas9 that will assist in treatment approaches for personalized medication.
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Affiliation(s)
- M Akhtar Anwar
- Department of Pharmacology and Toxicology, American University of Beirut, Beirut, Lebanon
| | - Chirine El-Baba
- Department of Biochemistry and Molecular Genetics, American University of Beirut, Beirut, Lebanon
| | - Muhammed H Elnaggar
- Biochemistry Department, Faculty of Science, Ain Shams University, Cairo, Egypt
| | - Yasmeen O Elkholy
- Microbiology Department, Faculty of Science, Cairo University, Giza, Egypt
| | - Mohamed Mottawea
- Faculty of Pharmacy, Modern University for Technology and Information, Cairo, Egypt
| | - Dina Johar
- Biomedical Sciences Program, Zewail University of Science and Technology, Giza, Egypt
| | | | - Firas Kobeissy
- Department of Biochemistry and Molecular Genetics, American University of Beirut, Beirut, Lebanon
| | - Charbel Moussalem
- Department of Surgery, American University of Beirut Medical Center, Beirut, Lebanon
| | - Elie Massaad
- Department of Surgery, American University of Beirut Medical Center, Beirut, Lebanon
| | - Ibrahim Omeis
- Department of Surgery, American University of Beirut Medical Center, Beirut, Lebanon
| | - Nadine Darwiche
- Department of Biochemistry and Molecular Genetics, American University of Beirut, Beirut, Lebanon.
| | - A H Eid
- Department of Pharmacology and Toxicology, American University of Beirut, Beirut, Lebanon; Department of Biomedical Sciences, Qatar University, Doha, Qatar.
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Ciocan-Cartita CA, Jurj A, Buse M, Gulei D, Braicu C, Raduly L, Cojocneanu R, Pruteanu LL, Iuga CA, Coza O, Berindan-Neagoe I. The Relevance of Mass Spectrometry Analysis for Personalized Medicine through Its Successful Application in Cancer "Omics". Int J Mol Sci 2019; 20:ijms20102576. [PMID: 31130665 PMCID: PMC6567119 DOI: 10.3390/ijms20102576] [Citation(s) in RCA: 22] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/11/2019] [Revised: 05/21/2019] [Accepted: 05/24/2019] [Indexed: 01/06/2023] Open
Abstract
Mass spectrometry (MS) is an essential analytical technology on which the emerging omics domains; such as genomics; transcriptomics; proteomics and metabolomics; are based. This quantifiable technique allows for the identification of thousands of proteins from cell culture; bodily fluids or tissue using either global or targeted strategies; or detection of biologically active metabolites in ultra amounts. The routine performance of MS technology in the oncological field provides a better understanding of human diseases in terms of pathophysiology; prevention; diagnosis and treatment; as well as development of new biomarkers; drugs targets and therapies. In this review; we argue that the recent; successful advances in MS technologies towards cancer omics studies provides a strong rationale for its implementation in biomedicine as a whole.
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Affiliation(s)
- Cristina Alexandra Ciocan-Cartita
- MEDFUTURE -Research Center for Advanced Medicine," Iuliu Hațieganu" University of Medicine and Pharmacy, 4-6 Louis Pasteur Street, 400349 Cluj-Napoca, Romania.
| | - Ancuța Jurj
- Research Center for Functional Genomics, Biomedicine and Translational Medicine," Iuliu Hațieganu" University of Medicine and Pharmacy.
| | - Mihail Buse
- MEDFUTURE -Research Center for Advanced Medicine," Iuliu Hațieganu" University of Medicine and Pharmacy, 4-6 Louis Pasteur Street, 400349 Cluj-Napoca, Romania.
| | - Diana Gulei
- MEDFUTURE -Research Center for Advanced Medicine," Iuliu Hațieganu" University of Medicine and Pharmacy, 4-6 Louis Pasteur Street, 400349 Cluj-Napoca, Romania.
| | - Cornelia Braicu
- Research Center for Functional Genomics, Biomedicine and Translational Medicine," Iuliu Hațieganu" University of Medicine and Pharmacy.
| | - Lajos Raduly
- Research Center for Functional Genomics, Biomedicine and Translational Medicine," Iuliu Hațieganu" University of Medicine and Pharmacy.
| | - Roxana Cojocneanu
- Research Center for Functional Genomics, Biomedicine and Translational Medicine," Iuliu Hațieganu" University of Medicine and Pharmacy.
| | - Lavinia Lorena Pruteanu
- MEDFUTURE -Research Center for Advanced Medicine," Iuliu Hațieganu" University of Medicine and Pharmacy, 4-6 Louis Pasteur Street, 400349 Cluj-Napoca, Romania.
| | - Cristina Adela Iuga
- MEDFUTURE -Research Center for Advanced Medicine," Iuliu Hațieganu" University of Medicine and Pharmacy, 4-6 Louis Pasteur Street, 400349 Cluj-Napoca, Romania.
- Department of Pharmaceutical Analysis, Faculty of Pharmacy, "Iuliu Hațieganu" University of Medicine and Pharmacy, 6 Louis Pasteur Street, 400349 Cluj-Napoca.
| | - Ovidiu Coza
- Department of Oncology, "Iuliu Hațieganu" University of Medicine and Pharmacy, 34-36 Republicii Street, 400015 Cluj-Napoca, Romania.
- Department of Radiotherapy with High Energies and Brachytherapy, Oncology Institute "Prof. Dr. Ion Chiricuta", 34-36 Republicii Street, 400015 Cluj-Napoca.
| | - Ioana Berindan-Neagoe
- MEDFUTURE -Research Center for Advanced Medicine," Iuliu Hațieganu" University of Medicine and Pharmacy, 4-6 Louis Pasteur Street, 400349 Cluj-Napoca, Romania.
- Research Center for Functional Genomics, Biomedicine and Translational Medicine," Iuliu Hațieganu" University of Medicine and Pharmacy.
- Department of Functional Genomics and Experimental Pathology, Ion Chiricuțǎ Oncology Institute, 34-36 Republicii Street, 400015 Cluj-Napoca.
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18
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Rossowska J, Anger N, Szczygieł A, Mierzejewska J, Pajtasz-Piasecka E. Reprogramming the murine colon cancer microenvironment using lentivectors encoding shRNA against IL-10 as a component of a potent DC-based chemoimmunotherapy. JOURNAL OF EXPERIMENTAL & CLINICAL CANCER RESEARCH : CR 2018; 37:126. [PMID: 29954431 PMCID: PMC6025815 DOI: 10.1186/s13046-018-0799-y] [Citation(s) in RCA: 24] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 05/05/2018] [Accepted: 06/11/2018] [Indexed: 01/07/2023]
Abstract
Background The excessive amounts of immunosuppressive factors present in a tumor microenvironment (TME) reduce the effectiveness of cancer vaccines. The main objective of our research was to improve the effectiveness of dendritic cell (DC)-based immunotherapy or chemoimmunotherapy composed of cyclophosphamide (CY) and DCs by application of lentivectors encoding shRNA specific to IL-10 (shIL10 LVs) in murine colon carcinoma MC38 model. Methods The efficacy of shIL10 LVs in silencing of IL-10 expression was measured both in vitro and in vivo using Real-Time PCR and ELISA assays. In addition, the influence of intratumorally inoculated lentivectors on MC38 tumor microenvironment was examined using flow cytometry method. The effect of applied therapeutic schemes was determined by measurement of tumor growth inhibition and activation state of local and systemic immune response. Results We observed that intratumorally inoculated shIL10 LVs transduced tumor and TME-infiltrating cells and reduced the secretion of IL-10. Application of shIL10 LVs for three consecutive weeks initiated tumor growth inhibition, whereas treatment with shIL10 LVs and BMDC/TAg did not enhance the antitumor effect. However, when pretreatment with CY was introduced to the proposed scheme, we noticed high MC38 tumor growth inhibition accompanied by reduction of MDSCs and Tregs in TME, as well as activation of potent local and systemic Th1-type antitumor response. Conclusions The obtained data shows that remodeling of TME by shIL10 LVs and CY enhances DC activity and supports them during regeneration and actuation of a potent antitumor response. Therefore, therapeutic strategies aimed at local IL-10 elimination using lentiviral vectors should be further investigated in context of combined chemoimmunotherapies. Electronic supplementary material The online version of this article (10.1186/s13046-018-0799-y) contains supplementary material, which is available to authorized users.
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Affiliation(s)
- Joanna Rossowska
- Hirszfeld Institute of Immunology and Experimental Therapy, Polish Academy of Sciences, ul. R. Weigla 12, 53-114, Wroclaw, Poland.
| | - Natalia Anger
- Hirszfeld Institute of Immunology and Experimental Therapy, Polish Academy of Sciences, ul. R. Weigla 12, 53-114, Wroclaw, Poland
| | - Agnieszka Szczygieł
- Hirszfeld Institute of Immunology and Experimental Therapy, Polish Academy of Sciences, ul. R. Weigla 12, 53-114, Wroclaw, Poland
| | - Jagoda Mierzejewska
- Hirszfeld Institute of Immunology and Experimental Therapy, Polish Academy of Sciences, ul. R. Weigla 12, 53-114, Wroclaw, Poland
| | - Elżbieta Pajtasz-Piasecka
- Hirszfeld Institute of Immunology and Experimental Therapy, Polish Academy of Sciences, ul. R. Weigla 12, 53-114, Wroclaw, Poland
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