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Jo A, Shoji T, Otsuka H, Abe M, Tatsuki S, Chiba Y, Sato S, Takatori E, Kaido Y, Nagasawa T, Kagabu M, Baba T. Treatment strategies for advanced and recurrent endometrial cancer using immune checkpoint inhibitors. Int J Clin Oncol 2025; 30:229-240. [PMID: 39812928 DOI: 10.1007/s10147-024-02689-8] [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: 08/02/2024] [Accepted: 12/30/2024] [Indexed: 01/16/2025]
Abstract
Doxorubicin + cisplatin and paclitaxel + carboplatin are standard chemotherapy regimens for endometrial cancer. The development of PD-1 and PDL-1 antibody drugs has led to the use of these agents for endometrial cancer in other countries. The KEYNOTE-775 trial for advanced or recurrent endometrial cancer demonstrated the benefits of pembrolizumab and lenvatinib combination therapy, and the results of this trial led to the approval of its coverage for recurrent cancer by the Japanese health insurance system. Currently, treatment with immune checkpoint inhibitors is transitioning from second-line to first-line therapy. In a global randomized phase III study, the drugs dostarlimab, durvalumab, and atezolizumab, which are not yet approved in Japan, showed better results in the study arms than in the control arm. Additionally, biomarkers have been developed for endometrial cancer, enabling gynecologists to pursue treatment options based on the biomarkers detected for better treatment outcomes. In this article, we review the clinical trials of immune checkpoint inhibitors for advanced or recurrent endometrial cancer.
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Affiliation(s)
- Ami Jo
- Department of Obstetrics and Gynecology, Iwate Medical University School of Medicine, 2-1-1, Idaidori, Yahaba, Iwate, 028-3695, Japan
| | - Tadahiro Shoji
- Department of Obstetrics and Gynecology, Iwate Medical University School of Medicine, 2-1-1, Idaidori, Yahaba, Iwate, 028-3695, Japan.
| | - Haruka Otsuka
- Department of Obstetrics and Gynecology, Iwate Medical University School of Medicine, 2-1-1, Idaidori, Yahaba, Iwate, 028-3695, Japan
| | - Marina Abe
- Department of Obstetrics and Gynecology, Iwate Medical University School of Medicine, 2-1-1, Idaidori, Yahaba, Iwate, 028-3695, Japan
| | - Shunsuke Tatsuki
- Department of Obstetrics and Gynecology, Iwate Medical University School of Medicine, 2-1-1, Idaidori, Yahaba, Iwate, 028-3695, Japan
| | - Yohei Chiba
- Department of Obstetrics and Gynecology, Iwate Medical University School of Medicine, 2-1-1, Idaidori, Yahaba, Iwate, 028-3695, Japan
| | - Sho Sato
- Department of Obstetrics and Gynecology, Iwate Medical University School of Medicine, 2-1-1, Idaidori, Yahaba, Iwate, 028-3695, Japan
| | - Eriko Takatori
- Department of Obstetrics and Gynecology, Iwate Medical University School of Medicine, 2-1-1, Idaidori, Yahaba, Iwate, 028-3695, Japan
| | - Yoshitaka Kaido
- Department of Obstetrics and Gynecology, Iwate Medical University School of Medicine, 2-1-1, Idaidori, Yahaba, Iwate, 028-3695, Japan
| | - Takayuki Nagasawa
- Department of Obstetrics and Gynecology, Iwate Medical University School of Medicine, 2-1-1, Idaidori, Yahaba, Iwate, 028-3695, Japan
| | - Masahiro Kagabu
- Department of Obstetrics and Gynecology, Iwate Medical University School of Medicine, 2-1-1, Idaidori, Yahaba, Iwate, 028-3695, Japan
| | - Tsukasa Baba
- Department of Obstetrics and Gynecology, Iwate Medical University School of Medicine, 2-1-1, Idaidori, Yahaba, Iwate, 028-3695, Japan
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Cao Z, Deng K, Jiang J, Tian K, Wang B. Combined treatment of small cell lung cancer using radiotherapy and immunotherapy: Challenges and updates. Biomed Pharmacother 2025; 182:117727. [PMID: 39675137 DOI: 10.1016/j.biopha.2024.117727] [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: 09/18/2024] [Revised: 11/17/2024] [Accepted: 12/03/2024] [Indexed: 12/17/2024] Open
Abstract
Currently, chemotherapy remains the standard first- and second-line treatment for small cell lung cancer (SCLC). Research concerning immunotherapy has brought about a remarkable development in the treatment pattern of SCLC. Atirizumab, duvalizumab, atezolizumab, and serplulimab can significantly improve the clinical outcomes of SCLC. Given the rapidly evolving concept that combining immunotherapy with radiotherapy can increase therapeutic effectiveness, clinicians are devoted to further improving local tumor control by integrating immunotherapy with radiotherapy. This paper reviews the research progress in this field to date and explores ways to further enhance the efficacy of this combination therapy. We first discussed that immunotherapy combined with radiotherapy can improve the abscopal effect, progression-free survival, and overall survival rates of SCLC patients. Then, the biomarkers related to the radiation immune microenvironment, such as programmed death ligand-1 (PD-L1), tumor mutational burden (TMB), and the immune function of patients were discussed. Next, we explored the occurrence and underlying mechanisms of immune resistance during radiotherapy implementation. Finally, we clarified that the emerging trend of low-dose radiotherapy help overcome the inhibitory signals that limit T-cell infiltration in the tumor matrix. In summary, considering the rapid development of this field, these combined therapy strategies may have unlimited potential to further improve the efficacy of radiotherapy combined with immunotherapy for patients.
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Affiliation(s)
- Zhumin Cao
- Department of Oncology, The Seventh People's Hospital of Chongqing (Affiliated Central Hospital of Chongqing University of Technology), Chongqing 400054, China.
| | - Kai Deng
- Department of Oncology, The First Affiliated Hospital of Chongqing Medical and Pharmaceutical College, Chongqing 400061, China.
| | - Jinxiu Jiang
- Department of Oncology, The First Affiliated Hospital of Chongqing Medical and Pharmaceutical College, Chongqing 400061, China.
| | - Ke Tian
- Department of Oncology, The Seventh People's Hospital of Chongqing (Affiliated Central Hospital of Chongqing University of Technology), Chongqing 400054, China.
| | - Bin Wang
- Department of Oncology, The Seventh People's Hospital of Chongqing (Affiliated Central Hospital of Chongqing University of Technology), Chongqing 400054, China.
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Wang S, Nie F, Yin Q, Tian H, Gong P, Ju J, Liu J, Yang P, Yang C. Periodontitis promotes tumor growth and immune evasion via PD-1/PD-L1. Cancer Immunol Immunother 2024; 74:22. [PMID: 39535607 PMCID: PMC11561227 DOI: 10.1007/s00262-024-03865-5] [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: 08/31/2024] [Accepted: 10/16/2024] [Indexed: 11/16/2024]
Abstract
BACKGROUND Our study investigated the role of experimental periodontitis on tumor growth, local and systemic immunosuppressive status, and programmed death receptor 1 (PD-1) / programmed death ligand 1 (PD-L1) expression in oral squamous cell carcinoma (OSCC) and prostate cancer. METHODS Mouse oral or prostate cancer xenograft models were divided into control, periodontitis and periodontitis + anti-PD-1 groups. Tumor volume and weight were recorded and the levels of relevant immune-suppressive cells and T cells were detected by flow cytometry or immunofluorescence. THP-1 cells were stimulated using conditioned media of LPS-stimulated Cal-27 cells and PD-L1 expression was measured by quantitative real-time PCR, western blotting and immunofluorescence. Tumor specimens from OSCC patients with or without periodontitis were also collected for immunofluorescence. RESULTS Periodontitis significantly promoted tumor volume and weight. Compared to the control, the proportions of tumor-associated macrophages (TAMs), regulatory T cells (Tregs), PD-L1+TAMs and PD-1+CD8+T cells increased, while CD8+T cells decreased in the periodontitis group. Immunofluorescence demonstrated that there was an increase in PD-L1+TAMs and PD-1+CD8+T cells, but a decrease in IFN-γ+CD8+T cells in both xenografts and clinical OSCC samples with periodontitis. In vitro, LPS-stimulated Cal-27 cells had a stronger potential to induce PD-L1 expression in macrophages compared with unstimulated Cal-27 cells. And the promoting effect of periodontitis on tumor growth and immune evasion was significantly attenuated after anti-PD-1 therapy. CONCLUSION Periodontitis may facilitate tumor growth and immune escape evidenced by the increased immune-suppressive cells and the decreased functional T cells, via enhancing PD-1/PD-L1 expression in the tumor microenvironment.
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Affiliation(s)
- Suli Wang
- Department of Periodontology, School and Hospital of Stomatology, Cheeloo College of Medicine, Shandong University & Shandong Key Laboratory of Oral Tissue Regeneration & Shandong Engineering Research Center of Dental Materials and Oral Tissue Regeneration & Shandong Provincial Clinical Research Center for Oral Diseases, No. 44-1 Wenhua Road West, 250012, Jinan, Shandong, China
| | - Fujiao Nie
- Department of Periodontology, School and Hospital of Stomatology, Cheeloo College of Medicine, Shandong University & Shandong Key Laboratory of Oral Tissue Regeneration & Shandong Engineering Research Center of Dental Materials and Oral Tissue Regeneration & Shandong Provincial Clinical Research Center for Oral Diseases, No. 44-1 Wenhua Road West, 250012, Jinan, Shandong, China
| | - Qiuyue Yin
- Department of Periodontology, School and Hospital of Stomatology, Cheeloo College of Medicine, Shandong University & Shandong Key Laboratory of Oral Tissue Regeneration & Shandong Engineering Research Center of Dental Materials and Oral Tissue Regeneration & Shandong Provincial Clinical Research Center for Oral Diseases, No. 44-1 Wenhua Road West, 250012, Jinan, Shandong, China
| | - Haoyang Tian
- Department of Periodontology, School and Hospital of Stomatology, Cheeloo College of Medicine, Shandong University & Shandong Key Laboratory of Oral Tissue Regeneration & Shandong Engineering Research Center of Dental Materials and Oral Tissue Regeneration & Shandong Provincial Clinical Research Center for Oral Diseases, No. 44-1 Wenhua Road West, 250012, Jinan, Shandong, China
| | - Pizhang Gong
- Department of Periodontology, School and Hospital of Stomatology, Cheeloo College of Medicine, Shandong University & Shandong Key Laboratory of Oral Tissue Regeneration & Shandong Engineering Research Center of Dental Materials and Oral Tissue Regeneration & Shandong Provincial Clinical Research Center for Oral Diseases, No. 44-1 Wenhua Road West, 250012, Jinan, Shandong, China
| | - Jinhong Ju
- Department of Periodontology, School and Hospital of Stomatology, Cheeloo College of Medicine, Shandong University & Shandong Key Laboratory of Oral Tissue Regeneration & Shandong Engineering Research Center of Dental Materials and Oral Tissue Regeneration & Shandong Provincial Clinical Research Center for Oral Diseases, No. 44-1 Wenhua Road West, 250012, Jinan, Shandong, China
| | - Jiayi Liu
- Department of Periodontology, School and Hospital of Stomatology, Cheeloo College of Medicine, Shandong University & Shandong Key Laboratory of Oral Tissue Regeneration & Shandong Engineering Research Center of Dental Materials and Oral Tissue Regeneration & Shandong Provincial Clinical Research Center for Oral Diseases, No. 44-1 Wenhua Road West, 250012, Jinan, Shandong, China
| | - Pishan Yang
- Department of Periodontology, School and Hospital of Stomatology, Cheeloo College of Medicine, Shandong University & Shandong Key Laboratory of Oral Tissue Regeneration & Shandong Engineering Research Center of Dental Materials and Oral Tissue Regeneration & Shandong Provincial Clinical Research Center for Oral Diseases, No. 44-1 Wenhua Road West, 250012, Jinan, Shandong, China.
| | - Chengzhe Yang
- Department of Oral and Maxillofacial Surgery, Qilu Hospital of Shandong University, No. 107 Wenhua Road West, 250012, Jinan, Shandong, China.
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Rojas-Quintero J, Díaz MP, Palmar J, Galan-Freyle NJ, Morillo V, Escalona D, González-Torres HJ, Torres W, Navarro-Quiroz E, Rivera-Porras D, Bermúdez V. Car T Cells in Solid Tumors: Overcoming Obstacles. Int J Mol Sci 2024; 25:4170. [PMID: 38673757 PMCID: PMC11050550 DOI: 10.3390/ijms25084170] [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: 11/03/2023] [Revised: 03/12/2024] [Accepted: 03/13/2024] [Indexed: 04/28/2024] Open
Abstract
Chimeric antigen receptor T cell (CAR T cell) therapy has emerged as a prominent adoptive cell therapy and a therapeutic approach of great interest in the fight against cancer. This approach has shown notorious efficacy in refractory hematological neoplasm, which has bolstered its exploration in the field of solid cancers. However, successfully managing solid tumors presents considerable intrinsic challenges, which include the necessity of guiding the modified cells toward the tumoral region, assuring their penetration and survival in adverse microenvironments, and addressing the complexity of identifying the specific antigens for each type of cancer. This review focuses on outlining the challenges faced by CAR T cell therapy when used in the treatment of solid tumors, as well as presenting optimizations and emergent approaches directed at improving its efficacy in this particular context. From precise localization to the modulation of the tumoral microenvironment and the adaptation of antigen recognition strategies, diverse pathways will be examined to overcome the current limitations and buttress the therapeutic potential of CAR T cells in the fight against solid tumors.
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Affiliation(s)
- Joselyn Rojas-Quintero
- Medicine, Pulmonary, Critical Care, and Sleep Medicine Department, Baylor College of Medicine, Houston, TX 77030, USA;
| | - María P. Díaz
- Facultad de Medicina, Centro de Investigaciones Endocrino—Metabólicas, Universidad del Zulia, Maracaibo 4001, Venezuela (J.P.); (V.M.); (D.E.); (W.T.)
| | - Jim Palmar
- Facultad de Medicina, Centro de Investigaciones Endocrino—Metabólicas, Universidad del Zulia, Maracaibo 4001, Venezuela (J.P.); (V.M.); (D.E.); (W.T.)
| | - Nataly J. Galan-Freyle
- Centro de Investigaciones en Ciencias de la Vida, Universidad Simón Bolívar, Barranquilla 080002, Colombia; (N.J.G.-F.); (E.N.-Q.)
| | - Valery Morillo
- Facultad de Medicina, Centro de Investigaciones Endocrino—Metabólicas, Universidad del Zulia, Maracaibo 4001, Venezuela (J.P.); (V.M.); (D.E.); (W.T.)
| | - Daniel Escalona
- Facultad de Medicina, Centro de Investigaciones Endocrino—Metabólicas, Universidad del Zulia, Maracaibo 4001, Venezuela (J.P.); (V.M.); (D.E.); (W.T.)
| | | | - Wheeler Torres
- Facultad de Medicina, Centro de Investigaciones Endocrino—Metabólicas, Universidad del Zulia, Maracaibo 4001, Venezuela (J.P.); (V.M.); (D.E.); (W.T.)
| | - Elkin Navarro-Quiroz
- Centro de Investigaciones en Ciencias de la Vida, Universidad Simón Bolívar, Barranquilla 080002, Colombia; (N.J.G.-F.); (E.N.-Q.)
- Facultad de Ciencias Básicas y Biomédicas, Barranquilla 080002, Colombia
| | - Diego Rivera-Porras
- Facultad de Ciencias Jurídicas y Sociales, Universidad Simón Bolívar, Cúcuta 540001, Colombia;
| | - Valmore Bermúdez
- Centro de Investigaciones en Ciencias de la Vida, Universidad Simón Bolívar, Barranquilla 080002, Colombia; (N.J.G.-F.); (E.N.-Q.)
- Facultad de Ciencias de la Salud, Universidad Simón Bolívar, Barranquilla 080002, Colombia;
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Chen M, Wang S. Preclinical development and clinical studies of targeted JAK/STAT combined Anti-PD-1/PD-L1 therapy. Int Immunopharmacol 2024; 130:111717. [PMID: 38387193 DOI: 10.1016/j.intimp.2024.111717] [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: 11/13/2023] [Revised: 02/14/2024] [Accepted: 02/15/2024] [Indexed: 02/24/2024]
Abstract
Programmed cell death protein 1 (PD-1) binds to its ligand to help tumours evade the immune system and promote tumour progression. Although anti-PD-1/PD-L1 therapies show powerful effects in some patients, most patients are unable to benefit from this treatment due to treatment resistance. Therefore, it is important to overcome tumour resistance to PD-1/PD-L1 blockade. There is substantial evidence suggesting that the JAK/STAT signalling pathway plays a significant role in PD-1/PD-L1 expression and anti-PD-1/PD-L1 treatment. Herein, we describe the effects of the JAK/STAT signalling pathway on PD-1/PD-L1. Subsequently, the relationship between molecular mutations in the JAK/STAT signalling pathway and immune resistance was analysed. Finally, the latest advancements in drugs targeting the JAK/STAT pathway combined with PD1/PD-L1 inhibitors are summarised.
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Affiliation(s)
- Miaomiao Chen
- Department of Oncology, Shengjing Hospital of China Medical University, Shenyang, 110004, China
| | - Siliang Wang
- Department of Oncology, Shengjing Hospital of China Medical University, Shenyang, 110004, China.
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Zhang Y, Li Z, Huang Y, Xu Y, Zou B. Nanotechnology and curcumin: a novel and promising approach in digestive cancer therapy. Nanomedicine (Lond) 2023; 18:2081-2099. [PMID: 38078442 DOI: 10.2217/nnm-2023-0213] [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] [Indexed: 01/19/2024] Open
Abstract
This study reviews the application of nanotechnology and curcumin, a polyphenol extracted from turmeric, in treating digestive cancers, one of the most common types of malignancies worldwide. Despite curcumin's potential for inhibiting tumor growth, its clinical application is hindered by issues such as poor solubility and bioavailability. Nanomedicine, with its unique ability to enhance drug delivery and reduce toxicity, offers a solution to these limitations. The paper focuses on the development of nanoformulations of curcumin, such as nanoparticles and liposomes, that improve its bioavailability and efficacy in treating digestive cancers, including liver and colorectal cancers. The study serves as a valuable reference for future research and development in this promising therapeutic approach.
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Affiliation(s)
- Yi Zhang
- Division of Thoracic Oncology, Department of Radiation Oncology, Cancer Center, West China Hospital, Sichuan University, Chengdu, 610041, PR China
| | - Zheng Li
- Division of Thoracic Oncology, Department of Radiation Oncology, Cancer Center, West China Hospital, Sichuan University, Chengdu, 610041, PR China
| | - Ying Huang
- College of Management, Sichuan Agricultural University, Chengdu, 611130, PR China
| | - Yong Xu
- Division of Thoracic Oncology, Department of Radiation Oncology, Cancer Center, West China Hospital, Sichuan University, Chengdu, 610041, PR China
| | - Bingwen Zou
- Division of Thoracic Oncology, Department of Radiation Oncology, Cancer Center, West China Hospital, Sichuan University, Chengdu, 610041, PR China
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Ben Hamouda S, Essafi-Benkhadir K. Interplay between Signaling Pathways and Tumor Microenvironment Components: A Paradoxical Role in Colorectal Cancer. Int J Mol Sci 2023; 24:ijms24065600. [PMID: 36982677 PMCID: PMC10057671 DOI: 10.3390/ijms24065600] [Citation(s) in RCA: 19] [Impact Index Per Article: 9.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/17/2023] [Revised: 03/06/2023] [Accepted: 03/07/2023] [Indexed: 03/17/2023] Open
Abstract
The study of the tumor microenvironment (TME) has become an important part of colorectal cancer (CRC) research. Indeed, it is now accepted that the invasive character of a primary CRC is determined not only by the genotype of the tumor cells, but also by their interactions with the extracellular environment, which thereby orchestrates the development of the tumor. In fact, the TME cells are a double-edged sword as they play both pro- and anti-tumor roles. The interaction of the tumor-infiltrating cells (TIC) with the cancer cells induces the polarization of the TIC, exhibiting an antagonist phenotype. This polarization is controlled by a plethora of interconnected pro- and anti-oncogenic signaling pathways. The complexity of this interaction and the dual function of these different actors contribute to the failure of CRC control. Thus, a better understanding of such mechanisms is of great interest and provides new opportunities for the development of personalized and efficient therapies for CRC. In this review, we summarize the signaling pathways linked to CRC and their implication in the development or inhibition of the tumor initiation and progression. In the second part, we enlist the major components of the TME and discuss the complexity of their cells functions.
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Zou Y, Yaguchi T. Programmed cell death-1 blockade therapy in melanoma: Resistance mechanisms and combination strategies. Exp Dermatol 2023; 32:264-275. [PMID: 36645031 DOI: 10.1111/exd.14750] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/20/2022] [Revised: 01/11/2023] [Accepted: 01/12/2023] [Indexed: 01/17/2023]
Abstract
Melanoma is a highly aggressive tumor derived from melanocytes. In recent years, the incidence and mortality of melanoma have gradually increased, seriously threatening human health. Classic treatments like surgery, chemotherapy, and radiotherapy show very limited efficacy. Due to the high immunogenicity of melanoma cells, immune checkpoint inhibitors have received considerable attention as melanoma treatments. One such therapy is blockade of programmed cell death-1 (PD-1), which is one of the most important negative immune regulators and is mainly expressed on activated T cells. Disruption of the interactions between PD-1 and its ligands, programmed death-ligand 1 (PD-L1) or programmed death-ligand 2 (PD-L2) rejuvenates exhausted T cells and enhances antitumor immunity. Although PD-1 blockade therapy is widely used in melanoma, a substantial proportion of patients still show no response or short durations of remission. Recent researches have focused on revealing the underlying mechanisms for resistance to this treatment and improving its efficacy through combination therapy. Here, we will introduce the resistance mechanisms associated with PD-1 blockade therapy in melanoma and review the combination therapies available.
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Affiliation(s)
- Yixin Zou
- Division of Immunology and Genomic Medicine, Center for Cancer Immunotherapy and Immunobiology, Graduate School of Medicine, Kyoto University, Kyoto, Japan
| | - Tomonori Yaguchi
- Division of Immunology and Genomic Medicine, Center for Cancer Immunotherapy and Immunobiology, Graduate School of Medicine, Kyoto University, Kyoto, Japan
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Liu C, Yang M, Zhang D, Chen M, Zhu D. Clinical cancer immunotherapy: Current progress and prospects. Front Immunol 2022; 13:961805. [PMID: 36304470 PMCID: PMC9592930 DOI: 10.3389/fimmu.2022.961805] [Citation(s) in RCA: 101] [Impact Index Per Article: 33.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/05/2022] [Accepted: 09/26/2022] [Indexed: 11/13/2022] Open
Abstract
Immune checkpoint therapy via PD-1 antibodies has shown exciting clinical value and robust therapeutic potential in clinical practice. It can significantly improve progression-free survival and overall survival. Following surgery, radiotherapy, chemotherapy, and targeted therapy, cancer treatment has now entered the age of immunotherapy. Although cancer immunotherapy has shown remarkable efficacy, it also suffers from limitations such as irAEs, cytokine storm, low response rate, etc. In this review, we discuss the basic classification, research progress, and limitations of cancer immunotherapy. Besides, by combining cancer immunotherapy resistance mechanism with analysis of combination therapy, we give our insights into the development of new anticancer immunotherapy strategies.
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Affiliation(s)
- Chenglong Liu
- Minhang Hospital and Department of Pharmacology, School of Pharmacy, Fudan University, Shanghai, China
| | - Mengxuan Yang
- Minhang Hospital and Department of Pharmacology, School of Pharmacy, Fudan University, Shanghai, China
| | - Daizhou Zhang
- New Drug Evaluation Center, Shandong Academy of Pharmaceutical Science, Jinan, China
| | - Ming Chen
- Department of Laboratory Medicine, Sixth Affiliated Hospital of Yangzhou University, Yangzhou, China
- Department of Laboratory Medicine, Affiliated Taixing Hospital of Bengbu Medical College, Taizhou, China
| | - Di Zhu
- Minhang Hospital and Department of Pharmacology, School of Pharmacy, Fudan University, Shanghai, China
- New Drug Evaluation Center, Shandong Academy of Pharmaceutical Science, Jinan, China
- Shanghai Engineering Research Center of ImmunoTherapeutics, Fudan University, Shanghai, China
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10
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Nath P, Majumder D, Debnath R, Debnath M, Singh Sekhawat S, Maiti D. Immunotherapeutic potential of ethanolic olive leaves extract (EOLE) and IL-28B combination therapy in ENU induced animal model of leukemia. Cytokine 2022; 156:155913. [DOI: 10.1016/j.cyto.2022.155913] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/01/2021] [Revised: 04/24/2022] [Accepted: 05/16/2022] [Indexed: 11/28/2022]
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Kajihara R, Sakai H, Han Y, Amari K, Kawamoto M, Hakoyama Y, Nagashio S, Yamada SI, Sanjo H, Kurita H. Presence of periodontitis may synergistically contribute to cancer progression via Treg and IL-6. Sci Rep 2022; 12:11584. [PMID: 35804048 PMCID: PMC9270385 DOI: 10.1038/s41598-022-15690-w] [Citation(s) in RCA: 14] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/14/2022] [Accepted: 06/28/2022] [Indexed: 11/09/2022] Open
Abstract
A close causal relationship has been suggested to exist between cancer and periodontitis. We hypothesized that the immune surveillance system is impaired in patients with periodontitis, which contributes to cancer development and growth. Therefore, the present study investigated the relationship between immune surveillance mechanisms and periodontitis in cancer patients. The presence or absence of periodontitis was assessed and the peripheral blood (PB) concentrations of IL-6, immunosuppressive cytokines (VEGF, TGF-β1, and CCL22) and proportion of T regulatory cells (Treg, CD3 + CD4 + CD25 + Foxp3 +) were measured. Subjects were classified into the following four groups: non-cancer patients without periodontitis (C − P −), non-cancer patients with periodontitis (C − P +), cancer patients without periodontitis (C + P −), and cancer patients with periodontitis (C + P +). The results of a multivariate analysis showed that the PB concentration of IL-6 was significantly higher in C + than in C- and higher in C + P + than in C + P −. The PB proportion of Treg was significantly higher in C + P + than in C + P −, C − P + , and C − P −. The results of this study suggested that the presence of periodontitis and cancer synergistically increased Treg in PB, which may be one of the underlying causes of immunosuppression and immune evasion in cancer. It was also suggested that the presence of periodontal disease and/or cancer also increases IL-6 in PB, which would be associated with cancer progression. These results suggest the possibility that the presence of periodontitis might synergistically contribute to cancer progression.
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Affiliation(s)
- Ryo Kajihara
- Department of Dentistry and Oral Surgery, Shinshu University School of Medicine, 3-1-1, Asahi, Matsumoto, 390-8621, Japan
| | - Hironori Sakai
- Department of Dentistry and Oral Surgery, Shinshu University School of Medicine, 3-1-1, Asahi, Matsumoto, 390-8621, Japan.
| | - Yibing Han
- Department of Dentistry and Oral Surgery, Shinshu University School of Medicine, 3-1-1, Asahi, Matsumoto, 390-8621, Japan
| | - Kei Amari
- Department of Dentistry and Oral Surgery, Shinshu University School of Medicine, 3-1-1, Asahi, Matsumoto, 390-8621, Japan
| | - Makiko Kawamoto
- Department of Dentistry and Oral Surgery, Shinshu University School of Medicine, 3-1-1, Asahi, Matsumoto, 390-8621, Japan
| | - Yusuke Hakoyama
- Department of Dentistry and Oral Surgery, Shinshu University School of Medicine, 3-1-1, Asahi, Matsumoto, 390-8621, Japan
| | - Sachiho Nagashio
- Department of Dentistry and Oral Surgery, Shinshu University School of Medicine, 3-1-1, Asahi, Matsumoto, 390-8621, Japan
| | - Shin-Ichi Yamada
- Department of Dentistry and Oral Surgery, Shinshu University School of Medicine, 3-1-1, Asahi, Matsumoto, 390-8621, Japan
| | - Hideki Sanjo
- Department of Molecular and Cellular Immunology, Shinshu University School of Medicine, Matsumoto, Japan
| | - Hiroshi Kurita
- Department of Dentistry and Oral Surgery, Shinshu University School of Medicine, 3-1-1, Asahi, Matsumoto, 390-8621, Japan
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12
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Wang L, Zhu S, Zou C, Kou H, Xu M, Li J. Preparation and evaluation of the anti-cancer properties of RGD-modified curcumin-loaded chitosan/perfluorohexane nanocapsules in vitro. Heliyon 2022; 8:e09931. [PMID: 35865990 PMCID: PMC9294197 DOI: 10.1016/j.heliyon.2022.e09931] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/17/2022] [Revised: 05/31/2022] [Accepted: 07/07/2022] [Indexed: 11/26/2022] Open
Abstract
Curcumin (Cur) encapsulation in nanocapsules (NCs) could improve its availability and therapeutic antitumor efficacy. Cur-loaded chitosan/perfluorohexane (CS/PFH) nanocapsules (CS/PFH-Cur-NCs) were thus synthesized via a nanoemulsion process. To further enhance the selective tumor targeting ability of Cur-loaded NCs, a novel CS/PFH-Cur-NCs with conjugation of Arg-Gly-Asp (RGD) peptide (RGD-CS/PFH-Cur-NCs) were prepared in this study. The properties of these NCs were then explored through in vitro release experiments and confocal laser scanning microscopy-based analyses of the ability of these NCs to target MDA-MB-231 breast cancer cells. In addition, an MTT assay-based approach was used to compare the relative cytotoxic impact of CS/PFH-Cur-NCs and RGD-CS/PFH-Cur-NCs on these breast cancer cells. It was found that both CS/PFH-Cur-NCs and RGD-CS/PFH-Cur-NCs were smooth, relatively uniform, spheroid particles, with the latter being 531.20 ± 68.97 nm in size. These RGD-CS/PFH-Cur-NCs can be ideal for contrast imaging studies, and were better able to target breast cancer cells in comparison to CS/PFH-Cur-NCs. In addition, RGD-CS/PFH-Cur-NCs were observed to induce cytotoxic MDA-MB-231 cell death more swiftly in comparison to CS/PFH-Cur-NCs. These findings suggest that NC encapsulation and RGD surface modification can remarkably improve the anti-tumor efficacy of Cur. These novel NCs may thus manifest a significant potential value in the realm of image-guided cancer therapy, underscoring an important direction for future research.
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Affiliation(s)
- Liang Wang
- Department of Ultrasound, Qilu Hospital of Shandong University, Jinan 250012, China.,Department of Ultrasound, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou 325027, China
| | - Shixia Zhu
- Department of Ultrasound, Wenzhou Seventh People's Hospital, Wenzhou 325005, China
| | - Chunpeng Zou
- Department of Ultrasound, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou 325027, China
| | - Hongju Kou
- Department of Ultrasound, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou 325027, China
| | - Maosheng Xu
- Department of Ultrasound, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou 325027, China
| | - Jie Li
- Department of Ultrasound, Qilu Hospital of Shandong University, Jinan 250012, China
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13
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Li R, Liu X, Song C, Zhang W, Liu J, Jiao X, Yu Y, Zeng S, Chi J, Zhao Y, Ma G, Huo Y, Li M, Peng Z, Li G, Jiang J, Gao QL. Sintilimab combined with bevacizumab in relapsed/persistent ovarian clear cell carcinoma (INOVA): an investigator-initiated, multicentre clinical trial-a study protocol of clinical trial. BMJ Open 2022; 12:e058132. [PMID: 35613822 PMCID: PMC9131073 DOI: 10.1136/bmjopen-2021-058132] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/04/2022] Open
Abstract
BACKGROUND Ovarian clear cell carcinoma (OCCC) has an abysmal prognosis with a median overall survival (OS) of 25.3 months because of a low response to chemotherapy. The 5-year disease-specific survival rate after recurrence is 13.2%, with more than two-thirds of the patients dying within a year. Therefore, it is urgent to explore new therapeutic options for OCCC. Based on the characteristic immune-suppressive tumour microenvironment derived from the gene expression profile of OCCC, the combination of immunoantiangiogenesis therapy might have certain efficacy in recurrent/persistent OCCC. This trial aims to evaluate the efficacy and safety of sintilimab and bevacizumab in patients who have failed platinum-containing chemotherapy with recurrent or persistent OCCC. METHOD AND ANALYSIS In this multicentre, single-arm, open-label, investigator-initiated clinical trial, 38 patients will be assigned to receive sintilimab 200 mg plus bevacizumab 15 mg/kg every 3 weeks. The eligibility criteria include histologically diagnosed patients with recurrent or persistent OCCC who have been previously treated with at least one-line platinum-containing chemotherapy; patients with Eastern Cooperative Oncology Group (ECOG) performance status 0-2 with an expected survival greater than 12 weeks. The exclusion criteria include patients previously treated with immune checkpoint inhibitor and patients with contraindications of bevacizumab and sintilimab. The primary endpoint is the objective response rate. The secondary endpoints are progression-free survival, time to response, duration of response, disease control rate, OS, safety and quality of life. Statistical significance was defined as p<0.05. ETHICS AND DISSEMINATION This trial was approved by the Research Ethics Commission of Tongji Medical College of Huazhong University of Science and Technology (2020-S337). The protocol of this study is registered at www. CLINICALTRIALS gov. The trial results will be published in peer-reviewed journals and at conferences. TRIAL REGISTRATION NUMBER NCT04735861; Clinicaltrials. gov.
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Affiliation(s)
- Ruyuan Li
- Cancer Biology Research Center (Key Laboratory of the Ministry of Education), Tongji Hospital of Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China
| | - Xingyu Liu
- Cancer Biology Research Center (Key Laboratory of the Ministry of Education), Tongji Hospital of Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China
| | - Chunyan Song
- Cancer Biology Research Center (Key Laboratory of the Ministry of Education), Tongji Hospital of Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China
| | - Wei Zhang
- Cancer Biology Research Center (Key Laboratory of the Ministry of Education), Tongji Hospital of Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China
| | - Jiahao Liu
- Cancer Biology Research Center (Key Laboratory of the Ministry of Education), Tongji Hospital of Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China
| | - Xiaofei Jiao
- Cancer Biology Research Center (Key Laboratory of the Ministry of Education), Tongji Hospital of Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China
| | - Yang Yu
- Cancer Biology Research Center (Key Laboratory of the Ministry of Education), Tongji Hospital of Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China
| | - Shaoqing Zeng
- Cancer Biology Research Center (Key Laboratory of the Ministry of Education), Tongji Hospital of Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China
| | - Jianhua Chi
- Cancer Biology Research Center (Key Laboratory of the Ministry of Education), Tongji Hospital of Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China
| | - Yingjun Zhao
- Cancer Biology Research Center (Key Laboratory of the Ministry of Education), Tongji Hospital of Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China
| | - Guanchen Ma
- Cancer Biology Research Center (Key Laboratory of the Ministry of Education), Tongji Hospital of Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China
| | - Yabing Huo
- Cancer Biology Research Center (Key Laboratory of the Ministry of Education), Tongji Hospital of Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China
| | - Ming Li
- Cancer Biology Research Center (Key Laboratory of the Ministry of Education), Tongji Hospital of Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China
| | - Zikun Peng
- Cancer Biology Research Center (Key Laboratory of the Ministry of Education), Tongji Hospital of Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China
| | - Guiling Li
- Department of Gynecological Oncology, Wuhan Union Hospital, Wuhan, Hubei, China
| | - Jie Jiang
- Department of Obstetrics and Gynecology, Shandong University Qilu Hospital, Jinan, Shandong, China
| | - Qing-Lei Gao
- Cancer Biology Research Center (Key Laboratory of the Ministry of Education), Tongji Hospital of Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China
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14
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Sabbatino F, Liguori L, Pepe S, Ferrone S. Immune checkpoint inhibitors for the treatment of melanoma. Expert Opin Biol Ther 2022; 22:563-576. [PMID: 35130816 PMCID: PMC9038682 DOI: 10.1080/14712598.2022.2038132] [Citation(s) in RCA: 16] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/04/2022]
Abstract
INTRODUCTION : Immune checkpoint inhibitor (ICI) based immunotherapy is dramatically changing the management of many types of cancers including melanoma. In this malignancy, ICIs have been shown to prolong disease and progression free survival as well as overall survival of a percentage of treated patients, becoming the cornerstone of melanoma treatment. AREAS COVERED : In this review, first, we will describe the mechanisms of immune checkpoint activation and inhibition, second, we will summarize the results obtained with ICIs in melanoma treatment in terms of efficacy as well as toxicity, third, we will discuss the potential mechanisms of immune escape from ICI, and lastly, we will review the potential predictive biomarkers of clinical efficacy of ICI-based immunotherapy in melanoma. EXPERT OPINION : ICIs represent one of the pillars of melanoma treatment. The success of ICI-based therapy is limited by the development of escape mechanisms which allow melanoma cells to avoid recognition and destruction by immune cells. These results emphasize the need of additional studies to confirm the efficacy of therapies which combine different classes of ICIs as well as ICIs with other types of therapies. Furthermore, novel and more effective predictive biomarkers are needed to better stratify melanoma patients in order to define more precisely the therapeutic algorithms.
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Affiliation(s)
- Francesco Sabbatino
- Department of Medicine, Surgery and Dentistry 'Scuola Medica Salernitana', University of Salerno, Baronissi, Salerno, Italy 84131
| | - Luigi Liguori
- Department of Clinical Medicine and Surgery, University of Naples "Federico II", Naples, Italy 80131
| | - Stefano Pepe
- Department of Medicine, Surgery and Dentistry 'Scuola Medica Salernitana', University of Salerno, Baronissi, Salerno, Italy 84131
| | - Soldano Ferrone
- Division of Surgical Oncology, Department of Surgery, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114
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15
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Tang J, Li M, Zhao C, Shen D, Liu L, Zhang X, Wei L. Therapeutic DNA Vaccines against HPV-Related Malignancies: Promising Leads from Clinical Trials. Viruses 2022; 14:v14020239. [PMID: 35215833 PMCID: PMC8874761 DOI: 10.3390/v14020239] [Citation(s) in RCA: 26] [Impact Index Per Article: 8.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/20/2021] [Revised: 01/19/2022] [Accepted: 01/22/2022] [Indexed: 01/27/2023] Open
Abstract
In 2014 and 2021, two nucleic-acid vaccine candidates named MAV E2 and VGX-3100 completed phase III clinical trials in Mexico and U.S., respectively, for patients with human papillomavirus (HPV)-related, high-grade squamous intraepithelial lesions (HSIL). These well-tolerated but still unlicensed vaccines encode distinct HPV antigens (E2 versus E6+E7) to elicit cell-mediated immune responses; their clinical efficacy, as measured by HSIL regression or cure, was modest when compared with placebo or surgery (conization), but both proved highly effective in clearing HPV infection, which should help further optimize strategies for enhancing vaccine immunogenicity, toward an ultimate goal of preventing malignancies in millions of patients who are living with persistent, oncogenic HPV infection but are not expected to benefit from current, prophylactic vaccines. The major roadblocks to a highly efficacious and practical product remain challenging and can be classified into five categories: (i) getting the vaccines into the right cells for efficient expression and presentation of HPV antigens (fusion proteins or epitopes); (ii) having adequate coverage of oncogenic HPV types, beyond the current focus on HPV-16 and -18; (iii) directing immune protection to various epithelial niches, especially anogenital mucosa and upper aerodigestive tract where HPV-transformed cells wreak havoc; (iv) establishing the time window and vaccination regimen, including dosage, interval and even combination therapy, for achieving maximum efficacy; and (v) validating therapeutic efficacy in patients with poor prognosis because of advanced, recurrent or non-resectable malignancies. Overall, the room for improvements is still large enough that continuing efforts for research and development will very likely extend into the next decade.
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Affiliation(s)
- Jianming Tang
- Aeonvital Biomedical Research Institute, Beijing 102208, China; (L.L.); (X.Z.)
- Correspondence: or
| | - Mingzhu Li
- Department of Gynecology and Obstetrics, Peking University People’s Hospital, Beijing 100033, China; (M.L.); (C.Z.); (D.S.); (L.W.)
| | - Chao Zhao
- Department of Gynecology and Obstetrics, Peking University People’s Hospital, Beijing 100033, China; (M.L.); (C.Z.); (D.S.); (L.W.)
| | - Danhua Shen
- Department of Gynecology and Obstetrics, Peking University People’s Hospital, Beijing 100033, China; (M.L.); (C.Z.); (D.S.); (L.W.)
| | - Lei Liu
- Aeonvital Biomedical Research Institute, Beijing 102208, China; (L.L.); (X.Z.)
| | - Xiujun Zhang
- Aeonvital Biomedical Research Institute, Beijing 102208, China; (L.L.); (X.Z.)
| | - Lihui Wei
- Department of Gynecology and Obstetrics, Peking University People’s Hospital, Beijing 100033, China; (M.L.); (C.Z.); (D.S.); (L.W.)
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16
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Li JH, O’Sullivan TE. Back to the Future: Spatiotemporal Determinants of NK Cell Antitumor Function. Front Immunol 2022; 12:816658. [PMID: 35082797 PMCID: PMC8785903 DOI: 10.3389/fimmu.2021.816658] [Citation(s) in RCA: 5] [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: 11/17/2021] [Accepted: 12/16/2021] [Indexed: 12/12/2022] Open
Abstract
NK cells play a crucial role in host protection during tumorigenesis. Throughout tumor development, however, NK cells become progressively dysfunctional through a combination of dynamic tissue-specific and systemic factors. While a number of immunosuppressive mechanisms present within the tumor microenvironment have been characterized, few studies have contextualized the spatiotemporal dynamics of these mechanisms during disease progression and across anatomical sites. Understanding how NK cell immunosuppression evolves in these contexts will be necessary to optimize NK cell therapy for solid and metastatic cancers. Here, we outline the spatiotemporal determinants of antitumor NK cell regulation, including heterogeneous tumor architecture, temporal disease states, diverse cellular communities, as well as the complex changes in NK cell states produced by the sum of these higher-order elements. Understanding of the signals encountered by NK cells across time and space may reveal new therapeutic targets to harness the full potential of NK cell therapy for cancer.
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Affiliation(s)
- Joey H. Li
- Department of Microbiology, Immunology, and Molecular Genetics, David Geffen School of Medicine at the University of California, Los Angeles (UCLA), Los Angeles, CA, United States
- Medical Scientist Training Program, David Geffen School of Medicine at the University of California, Los Angeles (UCLA), Los Angeles, CA, United States
| | - Timothy E. O’Sullivan
- Department of Microbiology, Immunology, and Molecular Genetics, David Geffen School of Medicine at the University of California, Los Angeles (UCLA), Los Angeles, CA, United States
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17
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LI K, YUAN D, CHEN W, MA R, XIAN Y. (S)-(-)-N-[2-(3-Hydroxy-2-oxo-2,3-dihydro-1H-indol-3-yl)-ethyl]-acetamide inhibits colon cancer growth via the STAT1 pathway. FOOD SCIENCE AND TECHNOLOGY 2022. [DOI: 10.1590/fst.49121] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/21/2022]
Affiliation(s)
- Kang LI
- Xi'an Jiaotong University, China
| | | | - Wei CHEN
- Xi'an Jiaotong University, China
| | - Rulan MA
- Xi'an Jiaotong University, China
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18
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Watanabe K, Nishikawa H. Engineering strategies for broad application of TCR-T and CAR-T cell therapies. Int Immunol 2021; 33:551-562. [PMID: 34374779 DOI: 10.1093/intimm/dxab052] [Citation(s) in RCA: 26] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/22/2021] [Accepted: 08/09/2021] [Indexed: 12/19/2022] Open
Abstract
Adoptive cell therapy, including the transfer of tumor-infiltrating T lymphocytes after in vitro expansion or T cells redirected to tumor antigens using antigen-specific transgenic T cell receptor T cells (TCR-T cells) or chimeric antigen receptor T cells (CAR-T cells), has shown a significant clinical impact. Particularly, several types of CAR-T cell therapies have been approved for the treatment of hematological malignancies. The striking success of CAR-T cell therapies in hematological malignancies motivates their further expansion to a wide range of solid tumors, yet multiple obstacles, including the lack of proper target antigens exhibiting a tumor-specific expression pattern and the immunosuppressive tumor microenvironment (TME) impairing the effector functions of adoptively transferred T cells, have prevented clinical application. Gene engineering technologies such as the CRISPR/Cas9 system have enabled flexible reprograming of TCR/CAR-T cell signaling or loading genes that are targets of the tumor immunosuppression as a payload to overcome the difficulties. Here, we discuss recent advances in TCR/CAR-T cell engineering: various promising approaches to enhance the antitumor activity of adoptively transferred T cells in the TME for maximizing the efficacy and the safety of adoptive cell therapy are now being tested in the clinic, especially targeting solid tumors.
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Affiliation(s)
- Keisuke Watanabe
- Division of Cancer Immunology, Research Institute, National Cancer Center, Tokyo 104-0045, Japan
| | - Hiroyoshi Nishikawa
- Division of Cancer Immunology, Research Institute, National Cancer Center, Tokyo 104-0045, Japan.,Department of Immunology, Nagoya University Graduate School of Medicine, Nagoya 466-8550, Japan
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19
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Kichloo A, Albosta M, Dahiya D, Guidi JC, Aljadah M, Singh J, Shaka H, Wani F, Kumar A, Lekkala M. Systemic adverse effects and toxicities associated with immunotherapy: A review. World J Clin Oncol 2021; 12:150-163. [PMID: 33767971 PMCID: PMC7968107 DOI: 10.5306/wjco.v12.i3.150] [Citation(s) in RCA: 43] [Impact Index Per Article: 10.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/03/2020] [Revised: 01/21/2021] [Accepted: 02/20/2021] [Indexed: 02/06/2023] Open
Abstract
Immunotherapy is rapidly evolving secondary to the advent of newer immunotherapeutic agents and increasing approval of the current agents by the United States Food and Drug Administration to treat a wide spectrum of cancers. Immunotherapeutic agents have gained immense popularity due to their tumor-specific action. Immunotherapy is slowly transforming into a separate therapeutic entity, and the fifth pillar of management for cancers alongside surgery, radiotherapy, chemotherapy, and targeted therapy. However, like any therapeutic entity it has its own adverse effects. With the increasing use of immuno-therapeutic agents, it is vital for physicians to acquaint themselves with these adverse effects. The aim of this review is to investigate the common systemic adverse effects and toxicities associated with the use of different classes of immunotherapeutic agents. We provide an overview of potential adverse effects and toxicities associated with different classes of immunotherapeutic agents organized by organ systems, as well as an extensive discussion of the current recommendations for treatment and clinical trial data. As we continue to see increasing usage of these agents in clinical practice, it is vital for physicians to familiarize themselves with these effects.
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Affiliation(s)
- Asim Kichloo
- Department of Internal Medicine, Central Michigan University, Saginaw, MI 48603, United States
- Department of Internal Medicine, Samaritan Medical Center, Watertown, NY 13601, United States
| | - Michael Albosta
- Department of Internal Medicine, Central Michigan University, Saginaw, MI 48603, United States
| | - Dushyant Dahiya
- Department of Internal Medicine, Central Michigan University, Saginaw, MI 48603, United States
| | - Jean Claude Guidi
- Department of Internal Medicine, Samaritan Medical Center, Watertown, NY 13601, United States
| | - Michael Aljadah
- Department of Internal Medicine, Medical College of Wisconsin, Milwaukee, WI 53201, United States
| | - Jagmeet Singh
- Department of Nephrology, Guthrie Robert Packer Hospital, Sayre, PA 18840, United States
| | - Hafeez Shaka
- Department of Internal Medicine, John H Stroger Jr. Hospital of Cook County, Chicago, IL 60612, United States
| | - Farah Wani
- Department of Family Medicine, Samaritan Medical Center, Watertown, NY 13601, United States
| | - Akshay Kumar
- Department of Surgery, University of Pittsburgh, Pittsburgh, PA 15213, United States
| | - Manidhar Lekkala
- Department of Hematology and Oncology, University of Rochester Medical Center, Rochester, NY 14642, United States
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20
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Nishio H, Iwata T, Aoki D. Current status of cancer immunotherapy for gynecologic malignancies. Jpn J Clin Oncol 2021; 51:167-172. [PMID: 33244581 DOI: 10.1093/jjco/hyaa214] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/04/2020] [Accepted: 10/13/2020] [Indexed: 12/26/2022] Open
Abstract
Recent cancer immunotherapy development with immune checkpoint inhibitors has shown durable clinical responses in a wide variety of tumor types. These drugs targeting programmed cell death 1, its ligand programmed death ligand 1 and cytotoxic T cell lymphocyte-associated antigen 4 have revolutionized the field of cancer treatment. It is of significant interest in optimizing the immunotherapy for cancer patients beyond the conventional treatments such as surgery, chemotherapy and radiation. Many clinical trials evaluating the safety and efficacy of various combined regimens with immune checkpoint inhibitors have been reported and are in progress. Among gynecologic malignancy, endometrial cancers have distinct subtypes with microsatellite instability-high status and polymerase ɛ mutation. These types have been shown to immunogenic tumors and appropriated candidate for immune checkpoint inhibitors. Also, recurrent cervical cancer showed a promising objective response with single anti-PD1 Ab treatment. Despite their definite outcome and considerable potential of immunotherapy, not all patients received a survival benefit and further understanding of human tumor immunology is essential to improve this type of therapy. In this review, we have summarized the updated results of clinical trials of cancer immunotherapy for gynecologic malignancies and discussed the future perspectives.
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Affiliation(s)
- Hiroshi Nishio
- Department of Obstetrics and Gynecology, Keio University School of Medicine, Tokyo, Japan
| | - Takashi Iwata
- Department of Obstetrics and Gynecology, Keio University School of Medicine, Tokyo, Japan
| | - Daisuke Aoki
- Department of Obstetrics and Gynecology, Keio University School of Medicine, Tokyo, Japan
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21
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Pietrowska M, Zebrowska A, Gawin M, Marczak L, Sharma P, Mondal S, Mika J, Polańska J, Ferrone S, Kirkwood JM, Widlak P, Whiteside TL. Proteomic profile of melanoma cell-derived small extracellular vesicles in patients' plasma: a potential correlate of melanoma progression. J Extracell Vesicles 2021; 10:e12063. [PMID: 33613873 PMCID: PMC7876545 DOI: 10.1002/jev2.12063] [Citation(s) in RCA: 38] [Impact Index Per Article: 9.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/08/2020] [Revised: 12/07/2020] [Accepted: 01/12/2021] [Indexed: 02/04/2023] Open
Abstract
Molecular profiling of small extracellular vesicles (sEV) isolated from plasma of cancer patients emerges as promising strategy for biomarkers discovery. We investigated the proteomic profiles of sEV immunoselected using anti-CSPG4 antibodies from 15 melanoma patients' plasma. The proteomes of sEV separated into melanoma cell-derived (MTEX) and non-malignant cell-derived (NMTEX) were compared using high-resolution mass spectrometry. Paired analysis identified the MTEX-associated profile of 16 proteins that discriminated MTEX from NMETEX. We also identified the MTEX profile that discriminated between seven patients with no evidence of melanoma (NED) after therapy and eight with progressive disease (PD). Among 75 MTEX proteins overexpressed in PD patients, PDCD6IP (ALIX) had the highest discriminating value, while CNTN1 (contactin-1) was upregulated only in MTEX of NED patients. This is the first report documenting that proteomes of tumour-derived sEV in patients' plasma discriminate cancer from non-cancer and identify proteins with potential to serve as prognostic biomarkers in melanoma.
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Affiliation(s)
- Monika Pietrowska
- Maria Sklodowska‐Curie National Research Institute of OncologyGliwicePoland
| | - Aneta Zebrowska
- Maria Sklodowska‐Curie National Research Institute of OncologyGliwicePoland
| | - Marta Gawin
- Maria Sklodowska‐Curie National Research Institute of OncologyGliwicePoland
| | - Lukasz Marczak
- European Center for Bioinformatics and GenomicsInstitute of Bioorganic Chemistry PASPoznanPoland
| | - Priyanka Sharma
- UPMC Hillman Cancer CenterUniversity of Pittsburgh Cancer InstitutePittsburghPennsylvaniaUSA
| | - Sujan Mondal
- UPMC Hillman Cancer CenterUniversity of Pittsburgh Cancer InstitutePittsburghPennsylvaniaUSA
| | - Justyna Mika
- Department of Data Science and Engineering, Silesian University of TechnologyGliwicePoland
| | - Joanna Polańska
- Department of Data Science and Engineering, Silesian University of TechnologyGliwicePoland
| | - Soldano Ferrone
- Department of SurgeryHarvard Medical School, Massachusetts General HospitalBostonMassachusettsUSA
| | - John M. Kirkwood
- UPMC Hillman Cancer CenterUniversity of Pittsburgh Cancer InstitutePittsburghPennsylvaniaUSA,Department of MedicineUniversity of Pittsburgh School of MedicinePittsburghPennsylvaniaUSA
| | - Piotr Widlak
- Maria Sklodowska‐Curie National Research Institute of OncologyGliwicePoland
| | - Theresa L. Whiteside
- UPMC Hillman Cancer CenterUniversity of Pittsburgh Cancer InstitutePittsburghPennsylvaniaUSA,Department of PathologyUniversity of Pittsburgh School of MedicinePittsburghPennsylvaniaUSA
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22
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Casanova JL, Abel L. Lethal Infectious Diseases as Inborn Errors of Immunity: Toward a Synthesis of the Germ and Genetic Theories. ANNUAL REVIEW OF PATHOLOGY 2021; 16:23-50. [PMID: 32289233 PMCID: PMC7923385 DOI: 10.1146/annurev-pathol-031920-101429] [Citation(s) in RCA: 80] [Impact Index Per Article: 20.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
It was first demonstrated in the late nineteenth century that human deaths from fever were typically due to infections. As the germ theory gained ground, it replaced the old, unproven theory that deaths from fever reflected a weak personal or even familial constitution. A new enigma emerged at the turn of the twentieth century, when it became apparent that only a small proportion of infected individuals die from primary infections with almost any given microbe. Classical genetics studies gradually revealed that severe infectious diseases could be driven by human genetic predisposition. This idea gained ground with the support of molecular genetics, in three successive, overlapping steps. First, many rare inborn errors of immunity were shown, from 1985 onward, to underlie multiple, recurrent infections with Mendelian inheritance. Second, a handful of rare and familial infections, also segregating as Mendelian traits but striking humans resistant to other infections, were deciphered molecularly beginning in 1996. Third, from 2007 onward, a growing number of rare or common sporadicinfections were shown to result from monogenic, but not Mendelian, inborn errors. A synthesis of the hitherto mutually exclusive germ and genetic theories is now in view.
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Affiliation(s)
- Jean-Laurent Casanova
- St. Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller Branch, The Rockefeller University, New York, NY 10065, USA;
- Howard Hughes Medical Institute, New York, NY 10065, USA
- Laboratory of Human Genetics of Infectious Diseases, Necker Branch, INSERM U1163, Necker Hospital for Sick Children, 75015 Paris, France
- Paris University, Imagine Institute, 75015 Paris, France
- Pediatric Hematology-Immunology Unit, Necker Hospital for Sick Children, 75015 Paris, France
| | - Laurent Abel
- St. Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller Branch, The Rockefeller University, New York, NY 10065, USA;
- Laboratory of Human Genetics of Infectious Diseases, Necker Branch, INSERM U1163, Necker Hospital for Sick Children, 75015 Paris, France
- Paris University, Imagine Institute, 75015 Paris, France
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23
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Dahiya DS, Kichloo A, Singh J, Albosta M, Lekkala M. Current immunotherapy in gastrointestinal malignancies A Review. J Investig Med 2021; 69:689-696. [PMID: 33443046 DOI: 10.1136/jim-2020-001654] [Citation(s) in RCA: 16] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 12/09/2020] [Indexed: 12/24/2022]
Abstract
Immunotherapy is an extremely important breakthrough and an exciting new modality of treatment for a wide spectrum of cancers. It is focused around developing agents to stimulate or suppress the immune system, in a specific manner, to fight off a wide spectrum of diseases, particularly cancers. Traditional therapies available for the treatment of cancers include surgical intervention, chemotherapy, radiation therapy or a combination of these, which tend to be very non-specific. However, immunotherapy shows a stark difference from conventional therapy, in fact, that it has a high level of specificity for the tumor-specific antigens. The recent success of cancer immunotherapies in clinical trials is slowly revolutionizing the landscape for cancer therapy. The US Food and Drug Administration has approved numerous agents, after clinical trials showed promising results, for the treatment of multiple cancers. The role of immunotherapy in gastrointestinal cancers has also been very promising, particularly in patients with advanced metastatic disease or malignancies refractory to initial treatment. In this review of literature, we detail and discuss the immunotherapy agents approved for the treatment of GI cancers and glance at the future of immunotherapy for patients with these cancers.
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Affiliation(s)
| | - Asim Kichloo
- Department of Internal Medicine, CMU Medical Education Partners, Saginaw, Michigan, USA .,Department of Internal Medicine, Samaritan Medical Center, Watertown, New York, USA
| | - Jagmeet Singh
- Internal Medicine, Guthrie Healthcare System, Sayre, Pennsylvania, USA.,Department of Internal Medicine, Geisinger Commonwealth School of Medicine, Scranton, Pennsylvania, USA
| | - Michael Albosta
- Internal Medicine, Central Michigan University, Saginaw, Michigan, USA
| | - Manidhar Lekkala
- Hematology and Oncology, University of Rochester Medical Center, Rochester, New York, USA
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24
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Renin-Angiotensin System in the Tumor Microenvironment. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2021; 1277:105-114. [PMID: 33119868 DOI: 10.1007/978-3-030-50224-9_7] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/19/2022]
Abstract
For enhancing the antitumor effects of current immunotherapies including immune-checkpoint blockade, it is important to reverse cancer-induced immunosuppression. The renin-angiotensin system (RAS) controls systemic body fluid circulation; however, the presence of a local RAS in tumors has been reported. Furthermore, the local RAS in tumors influences various immune and interstitial cells and affects tumor immune response. RAS stimulation through the angiotensin II type 1 receptor has been reported to inhibit tumor immune response. Therefore, RAS inhibitors and combined treatment with immunotherapy are expected in the future. In this chapter, we provide a background on the RAS and describe the tumor environment with regard to the RAS and tumor immune response.
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25
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Dahiya DS, Wani F, Guidi JC, Kichloo A. Gastrointestinal Adverse Effects of Immunotherapeutic Agents: A Systematic Review. Gastroenterology Res 2020; 13:227-232. [PMID: 33447301 PMCID: PMC7781271 DOI: 10.14740/gr1340] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/06/2020] [Accepted: 12/05/2020] [Indexed: 12/26/2022] Open
Abstract
The utilization of immunotherapy is increasing to the point of becoming the fifth pillar of management alongside surgical intervention, chemotherapy, radiotherapy and targeted therapy. However, gastrointestinal adverse effects and toxicities have been frequently cited with its use. As per literature, the most common adverse effect of immune checkpoint inhibitors is watery and non-bloody diarrhea. Adoptive cell therapy can lead to delayed, on-target but off-tumor adverse effects which are unknown and may be life-threatening. The use of anti-angiogenic monoclonal antibodies can lead to bowel perforations, whereas epidermal growth factor receptor inhibitors and anti-HER2 agents are frequently associated with diarrhea. Minimal adverse effects have been associated with therapeutic cancer vaccines; however, additional studies are needed to determine their efficacy and potential toxicities. To provide an in-depth review of the gastrointestinal side effects of immunotherapeutic agents, we performed a thorough literature search using multiple online search engines such as PubMed, Google Scholar and Ovid MEDLINE, along with a review of the guidelines from the United States Food and Drug Administration (FDA) and the Cancer Research Institute on immunotherapy. In this systematic review, we detail the gastrointestinal adverse effects of immunotherapy and describe their management. With the advent of newer immunotherapeutic agents and the consistent approval of current agents by FDA for a wide spectrum of cancers, it is vital for physicians to familiarize themselves with their adverse effects for prompt diagnosis and early intervention to decrease adverse outcomes.
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Affiliation(s)
| | - Farah Wani
- Department of Family Medicine, Samaritan Medical Center, Watertown, NY, USA
| | - Jean Claude Guidi
- Department of Internal Medicine, Samaritan Medical Center, Watertown, NY, USA
| | - Asim Kichloo
- Department of Internal Medicine, Central Michigan University, Saginaw, MI, USA.,Department of Internal Medicine, Samaritan Medical Center, Watertown, NY, USA
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26
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Deciphering of Key Pharmacological Pathways of Poria Cocos Intervention in Breast Cancer Based on Integrated Pharmacological Method. EVIDENCE-BASED COMPLEMENTARY AND ALTERNATIVE MEDICINE 2020; 2020:4931531. [PMID: 33149754 PMCID: PMC7603580 DOI: 10.1155/2020/4931531] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 01/20/2020] [Revised: 08/25/2020] [Accepted: 09/27/2020] [Indexed: 12/12/2022]
Abstract
OBJECTIVE Poria cocos (Fuling), a natural plant, has recently emerged as a promising strategy for cancer treatment. However, the molecular mechanisms of Poria cocos action in breast cancer remain poorly understood. METHODS TCMSP database was used to screen the potential active ingredients in Poria cocos. GEO database was used to identify differentially expressed genes. Network pharmacology was used to identify the specific pathways and key target proteins related to breast cancer. Finally, molecular docking was used to validate the results. RESULTS In our study, 237 targets were predicted for 15 potential active ingredients found in Poria cocos. An interaction network of predicted targets and genes differentially regulated in breast cancers was constructed. Based on the constructed network and further analysis including network topology, KEGG, survival analysis, and gene set enrichment analysis, 3 primary nodes were identified as key potential targets that were significantly enriched in the PPAR signaling pathway. CONCLUSION The results showed that potential active ingredients of Poria cocos might interfere with breast cancer through synergistic regulation of PTGS2, ESR1, and FOS.
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27
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Hayakawa T, Yaguchi T, Kawakami Y. Enhanced anti-tumor effects of the PD-1 blockade combined with a highly absorptive form of curcumin targeting STAT3. Cancer Sci 2020; 111:4326-4335. [PMID: 33006786 PMCID: PMC7734012 DOI: 10.1111/cas.14675] [Citation(s) in RCA: 49] [Impact Index Per Article: 9.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/06/2020] [Revised: 09/23/2020] [Accepted: 09/24/2020] [Indexed: 12/22/2022] Open
Abstract
PD‐1/PD‐L1 immune checkpoint inhibitors are promising cancer immunotherapies however responses are still limited and the development of more effective combination immunotherapy is needed. We previously reported that STAT3 activation in cancer cells and immune cells was involved in immune‐resistant mechanisms. In this study, we evaluated the effect of highly absorptive forms of curcumin extracts and synthetic curcumin on anti‐tumor T cell responses. The curcumin po administration resulted in the significant augmentation of in vivo induction of tumor antigen‐specific T cells through restoration of dendritic cells (DCs) by inhibiting directly STAT3 in DCs and indirectly via reduced IL‐6 production from STAT3 activated cancer cells in 2 syngeneic MC38 and CT26 murine tumor models. Curcumin also showed direct DC enhancing activity and enhanced T cell induction for the immunized antigens in non‐tumor‐bearing mice and human hosts. Curcumin restored DC functions in xenogeneic nude mouse model implanted with high IL‐6‐producing human clear cell ovarian cancer cells. The combination of curcumin and PD‐1/PD‐L1 Abs demonstrated a synergistic anti‐tumor activity in MC38 murine tumor models. These results indicated that curcumin augments the induction of tumor antigen‐specific T cells by restoring the T cell stimulatory activity of DCs targeting activated STAT3 in both cancer cells and immune cells. Combination immunotherapy with curcumin and PD‐1/PD‐L1 Ab is an attractive strategy in the development of effective immunotherapy against various cancers.
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Affiliation(s)
- Taeko Hayakawa
- Division of Cellular Signaling, Institute for Advanced Medical Research, Keio University School of Medicine, Tokyo, Japan
| | - Tomonori Yaguchi
- Division of Cellular Signaling, Institute for Advanced Medical Research, Keio University School of Medicine, Tokyo, Japan
| | - Yutaka Kawakami
- Division of Cellular Signaling, Institute for Advanced Medical Research, Keio University School of Medicine, Tokyo, Japan.,Department of Immunology, School of Medicine, International University of Health and Welfare, Chiba, Japan
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28
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Padya BS, Pandey A, Pisay M, Koteshwara KB, Chandrashekhar Hariharapura R, Bhat KU, Biswas S, Mutalik S. Stimuli-responsive and cellular targeted nanoplatforms for multimodal therapy of skin cancer. Eur J Pharmacol 2020; 890:173633. [PMID: 33049302 DOI: 10.1016/j.ejphar.2020.173633] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/08/2020] [Revised: 09/29/2020] [Accepted: 10/05/2020] [Indexed: 12/15/2022]
Abstract
Interdisciplinary applications of nanopharmaceutical sciences have tremendous potential for enhancing pharmacokinetics, efficacy and safety of cancer therapy. The limitations of conventional therapeutic platforms used for skin cancer therapy have been largely overcome by the use of nanoplatforms. This review discusses various nanotechnological approaches experimented for the treatment of skin cancer. The review describes various polymeric, lipidic and inorganic nanoplatforms for efficient therapy of skin cancer. The stimuli-responsive nanoplatforms such as pH-responsive as well as temperature-responsive platforms have also been reviewed. Different strategies for potentiating the nanoparticles application for cancer therapy such as surface engineering, conjugation with drugs, stimulus-responsive and multimodal effect have also been discussed and compared with the available conventional treatments. Although, nanopharmaceuticals face challenges such as toxicity, cost and scale-up, efforts put-in to improve these drawbacks with continuous research would deliver exciting and promising results in coming days.
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Affiliation(s)
- Bharath Singh Padya
- Department of Pharmaceutics, Manipal College of Pharmaceutical Sciences, Manipal Academy of Higher Education, Manipal, Karnataka, 576104, India
| | - Abhijeet Pandey
- Department of Pharmaceutics, Manipal College of Pharmaceutical Sciences, Manipal Academy of Higher Education, Manipal, Karnataka, 576104, India
| | - Muralidhar Pisay
- Department of Pharmaceutics, Manipal College of Pharmaceutical Sciences, Manipal Academy of Higher Education, Manipal, Karnataka, 576104, India
| | - K B Koteshwara
- Department of Pharmaceutics, Manipal College of Pharmaceutical Sciences, Manipal Academy of Higher Education, Manipal, Karnataka, 576104, India
| | - Raghu Chandrashekhar Hariharapura
- Department of Pharmaceutical Biotechnology, Manipal College of Pharmaceutical Sciences, Manipal Academy of Higher Education, Manipal, Karnataka, 576104, India
| | - Kuruveri Udaya Bhat
- Department of Metallurgical and Materials Engineering, National Institute of Technology, Mangalore, Karnataka, 575025, India
| | - Swati Biswas
- Department of Pharmacy, Birla Institute of Technology & Science-Pilani, Hyderabad Campus, Hyderabad, Telangana, 500078, India
| | - Srinivas Mutalik
- Department of Pharmaceutics, Manipal College of Pharmaceutical Sciences, Manipal Academy of Higher Education, Manipal, Karnataka, 576104, India.
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29
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Shin AR, Lee SE, Choi H, Sohn HJ, Cho HI, Kim TG. An effective peptide vaccine strategy circumventing clonal MHC heterogeneity of murine myeloid leukaemia. Br J Cancer 2020; 123:919-931. [PMID: 32595211 PMCID: PMC7492404 DOI: 10.1038/s41416-020-0955-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/04/2020] [Revised: 05/04/2020] [Accepted: 06/04/2020] [Indexed: 11/27/2022] Open
Abstract
BACKGROUND Therapeutic cancer vaccines are an attractive approach for treating malignant tumours, and successful tumour eradication depends primarily on controlling tumour immunosuppression status as well as heterogeneity of tumour cells driven by epigenetic alterations. METHODS Peptide-loaded dendritic cell (DC) prime and non-infectious peptide booster heterologous immunisations were assessed for the immunogenicity of polo-like kinase-1 (PLK1)-derived peptides. Heterologous vaccination regimen targeting multiple shared tumour antigens simultaneously with PD-L1 blockade was assessed against murine myeloid leukaemia. RESULTS A synthetic PLK1122 (DSDFVFVVL)-based heterologous vaccination generated large numbers of long-lasting antigen-specific CD8 T-cells eliciting therapeutic effects against various established tumours. The therapeutic efficacy of single antigen-targeting PLK1122-based vaccine with sufficient endurance of PD-L1 blockade toward C1498 leukaemia relied on the heterogeneous clonal levels of MHC-I and PD-L1 expression. A novel multi-peptide-based vaccination targeting PLK1 and survivin simultaneously along with PD1 blockade led to complete tumour eradication and long-term survival in mice with clonally heterologous C1498 myeloid leukaemia. CONCLUSIONS Our findings suggest that PLK1 could be an attractive immunotherapeutic target antigen for cancer immunotherapy, and that similar strategies would be applicable for the optimisation of cancer vaccines for the treatment of numerous viral diseases and malignant tumours.
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Affiliation(s)
- A-Ri Shin
- Department of Microbiology and Immunology, College of Medicine, The Catholic University of Korea, Seoul, 06591, South Korea
| | - Sang-Eun Lee
- Department of Microbiology and Immunology, College of Medicine, The Catholic University of Korea, Seoul, 06591, South Korea
| | - Haeyoun Choi
- Department of Microbiology and Immunology, College of Medicine, The Catholic University of Korea, Seoul, 06591, South Korea
| | - Hyun-Jung Sohn
- Translational and Clinical Division, ViGenCell Inc., Seoul, 06591, South Korea
| | - Hyun-Il Cho
- Translational and Clinical Division, ViGenCell Inc., Seoul, 06591, South Korea.
- Catholic Hematopoietic Stem Cell Bank, College of Medicine, The Catholic University of Korea, Seoul, 06591, South Korea.
| | - Tai-Gyu Kim
- Department of Microbiology and Immunology, College of Medicine, The Catholic University of Korea, Seoul, 06591, South Korea.
- Catholic Hematopoietic Stem Cell Bank, College of Medicine, The Catholic University of Korea, Seoul, 06591, South Korea.
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30
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Sciammarella C, Luce A, Riccardi F, Mocerino C, Modica R, Berretta M, Misso G, Cossu AM, Colao A, Vitale G, Necas A, Fedacko J, Galdiero M, Correale P, Faggiano A, Caraglia M, Capasso A, Grimaldi A. Lanreotide Induces Cytokine Modulation in Intestinal Neuroendocrine Tumors and Overcomes Resistance to Everolimus. Front Oncol 2020; 10:1047. [PMID: 32766136 PMCID: PMC7379869 DOI: 10.3389/fonc.2020.01047] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/26/2020] [Accepted: 05/27/2020] [Indexed: 12/11/2022] Open
Abstract
Somatostatin analogs mantain their major role in the treatment of patients with advanced neuroendocrine tumors (NETs) and have multiple modulatory effects on the immune system. Here, we evaluated the effects of lanreotide treatment on expression of Th1, Th2 cytokine patterns in serum of patients with NETs and in bronchial and pancreatic NET cell lines. Our results showed that lanreotide treatment promoted a Th1 cytotoxic immune-phenotype in patients with NETs originated by intestinal sites. Similar results were obtained also in vitro where lanreotide induced expression of Th1 cytokines only in pancreatic and not in bronchial-derived NET cell lines. It seems, therefore, that cytokinomics can represent a useful tool for the identification of tumor biomarkers for the early diagnosis and evaluation of the response to therapy in NET patients. To avoid the drug-resistance induced by everolimus (mTOR inhibitor), we made the pancreatic NET cell line resistant to this drug. After treatment with lanreotide we found that the drug reduced its viability compared to that of sensitive cells. These data may have direct implications in design of future translation combination trial on NET patients.
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Affiliation(s)
- Concetta Sciammarella
- Department of Precision Medicine, University of Campania "Luigi Vanvitelli", Naples, Italy.,Department of Clinical Medicine and Surgery, University "Federico II" of Naples, Naples, Italy
| | - Amalia Luce
- Department of Precision Medicine, University of Campania "Luigi Vanvitelli", Naples, Italy
| | | | | | - Roberta Modica
- Department of Clinical Medicine and Surgery, University "Federico II" of Naples, Naples, Italy
| | - Massimiliano Berretta
- Department of Medical Oncology, Centro di Riferimento Oncologico, Istituto Nazionale Tumori CRO, Aviano, Italy
| | - Gabriella Misso
- Department of Precision Medicine, University of Campania "Luigi Vanvitelli", Naples, Italy
| | - Alessia Maria Cossu
- Laboratory of Precision and Molecular Oncology, Institute of Genetic Research, Biogem Scarl, Avellino, Italy
| | - Annamaria Colao
- Department of Clinical Medicine and Surgery, University "Federico II" of Naples, Naples, Italy
| | - Giovanni Vitale
- Laboratory of Geriatric and Oncologic Neuroendocrinology Research, Istituto Auxologico Italiano, IRCCS, Milan, Italy.,Department of Clinical Sciences and Community Health (DISCCO), University of Milan, Milan, Italy
| | - Alois Necas
- CEITEC - Central European Institute of Technology, University of Veterinary and Pharmaceutical Sciences Brno, Brno, Czechia
| | - Jan Fedacko
- 1st Department of Internal Medicine, Centre of Excellency for Atherosclerosis Research, University of Pavol Jozef Safarik, Košice, Slovakia
| | - Marilena Galdiero
- Department of Experimental Medicine, University of Campania "Luigi Vanvitelli", Naples, Italy
| | - Pierpaolo Correale
- Medical Oncology Unit, "Bianchi-Melacrino-Morelli" Grand Metropolitan Hospital, Reggio Calabria, Italy
| | - Antongiulio Faggiano
- Department of Experimental Medicine, Division of Endocrinology, Sapienza University of Rome, Rome, Italy
| | - Michele Caraglia
- Department of Precision Medicine, University of Campania "Luigi Vanvitelli", Naples, Italy.,Laboratory of Precision and Molecular Oncology, Institute of Genetic Research, Biogem Scarl, Avellino, Italy
| | - Anna Capasso
- Department of Oncology, Livestrong Cancer Institutes, Dell Medical School, The University of Texas, Austin, TX, United States
| | - Anna Grimaldi
- Department of Precision Medicine, University of Campania "Luigi Vanvitelli", Naples, Italy
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31
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Renin-Angiotensin System in Lung Tumor and Microenvironment Interactions. Cancers (Basel) 2020; 12:cancers12061457. [PMID: 32503281 PMCID: PMC7352181 DOI: 10.3390/cancers12061457] [Citation(s) in RCA: 30] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/16/2020] [Revised: 05/24/2020] [Accepted: 06/01/2020] [Indexed: 02/08/2023] Open
Abstract
The mechanistic involvement of the renin-angiotensin system (RAS) reaches beyond cardiovascular physiopathology. Recent knowledge pinpoints a pleiotropic role for this system, particularly in the lung, and mainly through locally regulated alternative molecules and secondary pathways. Angiotensin peptides play a role in cell proliferation, immunoinflammatory response, hypoxia and angiogenesis, which are critical biological processes in lung cancer. This manuscript reviews the literature supporting a role for the renin-angiotensin system in the lung tumor microenvironment and discusses whether blockade of this pathway in clinical settings may serve as an adjuvant therapy in lung cancer.
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32
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Kagabu M, Nagasawa T, Sato C, Fukagawa Y, Kawamura H, Tomabechi H, Takemoto S, Shoji T, Baba T. Immunotherapy for Uterine Cervical Cancer Using Checkpoint Inhibitors: Future Directions. Int J Mol Sci 2020; 21:E2335. [PMID: 32230938 PMCID: PMC7177858 DOI: 10.3390/ijms21072335] [Citation(s) in RCA: 48] [Impact Index Per Article: 9.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/27/2020] [Revised: 03/24/2020] [Accepted: 03/25/2020] [Indexed: 12/12/2022] Open
Abstract
Immune checkpoint inhibitors (ICIs) have demonstrated marked clinical effects worldwide, and "cancer immunotherapy" has been recognized as a feasible option for cancer treatment. Significant treatment responses have already been attained for malignant melanoma and lung cancer, ahead of gynecologic cancer. In cervical cancer, however, results are only available from phase II trials, not from phase III trials. Cervical cancer is a malignant tumor and is the fourth most common cancer among women worldwide. Since the introduction of angiogenesis inhibitors, treatment for recurrent and advanced cervical cancers has improved in the past five years, but median overall survival is 16.8 months for advanced cervical cancer, and all-stage five-year overall survival rate is 68%, indicating that treatment effects remain inadequate. For this reason, the development of new therapeutic approaches is imperative. We describe herein the KEYNOTE-158 and CheckMate 358 clinical trials, which were conducted for cervical cancer, and discuss future directions, including potential combinations with concurrent chemoradiation therapy (CCRT), as noted for other types of cancer.
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Affiliation(s)
- Masahiro Kagabu
- Department of Obstetrics and Gynecology, Iwate Medical University School of Medicine, Morioka, Iwate 028-3695, Japan; (T.N.); (C.S.); (H.K.); (Y.F.); (H.T.); (S.T.); (T.S.); (T.B.)
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33
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Immune-resistant mechanisms in cancer immunotherapy. Int J Clin Oncol 2020; 25:810-817. [PMID: 31919690 DOI: 10.1007/s10147-019-01611-x] [Citation(s) in RCA: 34] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/02/2019] [Accepted: 12/23/2019] [Indexed: 12/17/2022]
Abstract
Immune checkpoint inhibitors (ICI) such as PD-1/PD-L1 antibodies (Abs) and CTLA4 Abs and T cell-based adoptive cell therapies are effective for patients with various cancers. However, response rates of ICI monotherapies are still limited due to lack of immunogenic antigens and various immune-resistant mechanisms. The latter includes adaptive immune resistance that is caused by anti-tumor T cells (e.g. PD-L1 induced by IFN-γ from T cells) and primary immune resistance that is caused by cancer cells (e.g. immunosuppressive cytokines produced by cancer cells). Further understanding of the immune-resistant mechanisms, which may be possible through comparative analyses of responders and non-responders to the immunotherapies, will lead to the identification of new diagnostic biomarkers and therapeutic targets for development of effective cancer immuno therapies.
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34
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The clinicopathological and prognostic value of PD-L1 in urothelial carcinoma: a meta-analysis. Clin Exp Med 2019; 19:407-416. [DOI: 10.1007/s10238-019-00572-9] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/07/2018] [Accepted: 07/22/2019] [Indexed: 11/25/2022]
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35
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Liu J, Zhou J, Wu M, Hu C, Yang J, Li D, Wu P, Chen Y, Chen P, Lin S, Cui Y, Fu S, Wu J. Low-Dose Total Body Irradiation Can Enhance Systemic Immune Related Response Induced by Hypo-Fractionated Radiation. Front Immunol 2019; 10:317. [PMID: 30873170 PMCID: PMC6401363 DOI: 10.3389/fimmu.2019.00317] [Citation(s) in RCA: 21] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/11/2018] [Accepted: 02/06/2019] [Indexed: 12/20/2022] Open
Abstract
A systemic immune related response (SIME) of radiotherapy has been occasionally observed on metastatic tumors, but the clinical outcomes remain poor. Novel treatment approaches are therefore needed to improve SIME ratio. We used a combination of hypo-fractionated radiation therapy (H-RT) with low-dose total body irradiation (L-TBI) in a syngeneic mouse model of breast and colon carcinoma. The combination therapy of H-RT and L-TBI potentially enhanced SIME by infiltration of CD8+ T cell and altering the immunosuppressive microenvironment in non-irradiated subcutaneous tumor lesions. The frequency of IFN-γ, as a tumor-specific CD8+ T cells producing, significantly inhibited the secondary tumor growth of breast and colon. Our findings suggest that L-TBI could serve as a potential therapeutic agent for metastatic breast and colon cancer and, together with H-RT, their therapeutic potential is enhanced significantly.
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Affiliation(s)
- Jing Liu
- Department of Oncology, The Affiliated Hospital of Southwest Medical University, Nuclear Medicine and Molecular Imaging Key Laboratory of Sichuan Province, Luzhou, China
| | - Jie Zhou
- Department of Radiation Oncology, Sichuan Cancer Hospital & Institute, Sichuan Cancer Center, School of Medicine, University of Electronic Science and Technology of China, Chengdu, China
| | - Min Wu
- Department of Oncology, The Affiliated Hospital of Southwest Medical University, Nuclear Medicine and Molecular Imaging Key Laboratory of Sichuan Province, Luzhou, China
| | - ChuanFei Hu
- Department of Oncology, The Affiliated Hospital of Southwest Medical University, Nuclear Medicine and Molecular Imaging Key Laboratory of Sichuan Province, Luzhou, China
| | - Juan Yang
- Department of Oncology, The Affiliated Hospital of Southwest Medical University, Nuclear Medicine and Molecular Imaging Key Laboratory of Sichuan Province, Luzhou, China
| | - Dong Li
- Department of Oncology, The Affiliated Hospital of Southwest Medical University, Nuclear Medicine and Molecular Imaging Key Laboratory of Sichuan Province, Luzhou, China
| | - Peng Wu
- Department of Oncology, The Affiliated Hospital of Southwest Medical University, Nuclear Medicine and Molecular Imaging Key Laboratory of Sichuan Province, Luzhou, China
| | - Yue Chen
- Nuclear Medicine and Molecular Imaging Key Laboratory of Sichuan Province, Department of Nuclear Medicine, The Affiliated Hospital of Southwest Medical University, Luzhou, China
| | - Ping Chen
- Department of Oncology, The Affiliated Hospital of Southwest Medical University, Nuclear Medicine and Molecular Imaging Key Laboratory of Sichuan Province, Luzhou, China
| | - Sheng Lin
- Department of Oncology, The Affiliated Hospital of Southwest Medical University, Nuclear Medicine and Molecular Imaging Key Laboratory of Sichuan Province, Luzhou, China
| | - YongXia Cui
- Department of Oncology, The Affiliated Hospital of Southwest Medical University, Nuclear Medicine and Molecular Imaging Key Laboratory of Sichuan Province, Luzhou, China
| | - ShaoZhi Fu
- Department of Oncology, The Affiliated Hospital of Southwest Medical University, Nuclear Medicine and Molecular Imaging Key Laboratory of Sichuan Province, Luzhou, China
| | - JingBo Wu
- Department of Oncology, The Affiliated Hospital of Southwest Medical University, Nuclear Medicine and Molecular Imaging Key Laboratory of Sichuan Province, Luzhou, China
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36
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Liu Y, Yang Q, Cao L, Xu F. Analysis of Leukocyte Behaviors on Microfluidic Chips. Adv Healthc Mater 2019; 8:e1801406. [PMID: 30672149 DOI: 10.1002/adhm.201801406] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/02/2018] [Revised: 01/05/2019] [Indexed: 01/17/2023]
Abstract
The orchestration of massive leukocytes in the immune system protects humans from invading pathogens and abnormal cells in the body. So far, researches focusing on leukocyte behaviors are performed based on both in vivo and in vitro models. The in vivo animal models are usually less controllable due to their extreme complexity and nonignorable species issue. Therefore, many researchers turn to in vitro models. With the advances in micro/nanofabrication, the microfluidic chip has emerged as a novel platform for model construction in multiple biomedical research fields. Specifically, the microfluidic chip is used to study leukocyte behaviors, due to its incomparable advantages in high throughput, precise control, and flexible integration. Moreover, the small size of the microstructures on the microfluidic chip can better mimic the native microenvironment of leukocytes, which contributes to a more reliable recapitulation. Herein are reviewed the recent advances in microfluidic chip-based leukocyte behavior analysis to provide an overview of this field. Detailed discussions are specifically focused on host defense against pathogens, immunodiagnosis, and immunotherapy studies on microfluidic chips. Finally, the current technical challenges are discussed, as well as possible innovations in this field to improve the related applications.
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Affiliation(s)
- Yan Liu
- The Key Laboratory of Biomedical Information Engineering of Ministry of Education; School of Life Science and Technology; Xi'an Jiaotong University; Xi'an Shaanxi 710049 China
- Bioinspired Engineering and Biomechanics Center (BEBC); Xi'an Jiaotong University; Xi'an Shaanxi 710049 China
| | - Qingzhen Yang
- The Key Laboratory of Biomedical Information Engineering of Ministry of Education; School of Life Science and Technology; Xi'an Jiaotong University; Xi'an Shaanxi 710049 China
- Bioinspired Engineering and Biomechanics Center (BEBC); Xi'an Jiaotong University; Xi'an Shaanxi 710049 China
| | - Lei Cao
- The Key Laboratory of Biomedical Information Engineering of Ministry of Education; School of Life Science and Technology; Xi'an Jiaotong University; Xi'an Shaanxi 710049 China
- Bioinspired Engineering and Biomechanics Center (BEBC); Xi'an Jiaotong University; Xi'an Shaanxi 710049 China
| | - Feng Xu
- The Key Laboratory of Biomedical Information Engineering of Ministry of Education; School of Life Science and Technology; Xi'an Jiaotong University; Xi'an Shaanxi 710049 China
- Bioinspired Engineering and Biomechanics Center (BEBC); Xi'an Jiaotong University; Xi'an Shaanxi 710049 China
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Dimitriou N, Felekouras E, Karavokyros I, Alexandrou A, Pikoulis E, Griniatsos J. Neutrophils to lymphocytes ratio as a useful prognosticator for stage II colorectal cancer patients. BMC Cancer 2018; 18:1202. [PMID: 30509242 PMCID: PMC6278137 DOI: 10.1186/s12885-018-5042-x] [Citation(s) in RCA: 45] [Impact Index Per Article: 6.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/07/2018] [Accepted: 11/05/2018] [Indexed: 12/14/2022] Open
Abstract
Background The incidence of colorectal cancer (CRC) is expected to increase by 80% in year 2035. Even though advantages in treatment of CRC have being made over the last decades, the outcome remains poor. Recently, several inflammatory markers including pretreatment neutrophil to lymphocyte ratio (NLR), have being used as prognostic factors, since host inflammatory response to cancer is believed to determine disease progression. The aim of this study is to evaluate the prognostic significance of pretreatment NLR, in terms of overall survival (OS), 5-year survival, disease-free survival (DFS) and recurrence, in CRC patients who underwent curative resection. Methods We retrospectively reviewed 296 patients, who were submitted to elective surgery as first therapeutic option in curative intent, between January 2010 and December 2015. Pretreatment NLR, as well as demographics, clinical, histopathologic, and laboratory data were analyzed. Univariate and multivariate analyses were conducted to identify prognostic factors associated with OS, 5-year survival, DFS and recurrence. Results The cutoff point of NLR was calculated with Kaplan-Meier curves and log-rank test to 4.7. Univariate and multivariate analyses disclosed elevated NLR as a significant dismal prognostic factor for DFS (HR 1.88; 95% CI 1.01–3.52; p = 0.048), 5-year survival (HR 2.14; 95% CI 1.12–4.10; p = 0.021) and OS (HR 2.11; 95% CI 1.11–4.03; p = 0.023). In a subgroup analysis, in patients with stage II CRC, NLR > 4.7 was a stronger poor predictor for DFS (HR 2.76; 95% CI 1.07–7.13; p = 0.036), 5-year survival (HR 3.84; 95% CI 1.39–10.63; p = 0.01) and OS (HR 3.62; 95% CI 1.33–4.82; p = 0.012). After adjusting stage for gender, age, location of the primary tumor, differentiation, as well as the presence of perineural, vascular, and lymphovascular invasion, the significance of NLR > 4.7 became more prominent for DFS (HR 2.85; 95% CI 1.21–6.73; p = 0.0176), 5-year survival (HR 4.06; 95% CI 1.66–9.93; p = 0.002) and OS (HR 4.07; 95% CI 1.69–9.91; p = 0.002) in stage II patients. Conclusion Pretreatment NLR > 4.7 is a poor prognostic factor for DFS, 5-year survival and OS in CRC patients undergoing curative resection. The dismal prognostic effect of NRL is magnified in Stage II CRC patients.
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Affiliation(s)
- Nikoletta Dimitriou
- Department of Surgery, National and Kapodistrian University of Athens, Medical School, Laiko Hospital, Agiou Thoma 17 str, GR 115-27, Athens, Greece.
| | - Evangelos Felekouras
- Department of Surgery, National and Kapodistrian University of Athens, Medical School, Laiko Hospital, Agiou Thoma 17 str, GR 115-27, Athens, Greece
| | - Ioannis Karavokyros
- Department of Surgery, National and Kapodistrian University of Athens, Medical School, Laiko Hospital, Agiou Thoma 17 str, GR 115-27, Athens, Greece
| | - Andreas Alexandrou
- Department of Surgery, National and Kapodistrian University of Athens, Medical School, Laiko Hospital, Agiou Thoma 17 str, GR 115-27, Athens, Greece
| | - Emmanuel Pikoulis
- Department of Surgery, National and Kapodistrian University of Athens, Medical School, Laiko Hospital, Agiou Thoma 17 str, GR 115-27, Athens, Greece
| | - John Griniatsos
- Department of Surgery, National and Kapodistrian University of Athens, Medical School, Laiko Hospital, Agiou Thoma 17 str, GR 115-27, Athens, Greece
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Oda K, Hamanishi J, Matsuo K, Hasegawa K. Genomics to immunotherapy of ovarian clear cell carcinoma: Unique opportunities for management. Gynecol Oncol 2018; 151:381-389. [PMID: 30217369 PMCID: PMC7526052 DOI: 10.1016/j.ygyno.2018.09.001] [Citation(s) in RCA: 100] [Impact Index Per Article: 14.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/06/2018] [Revised: 08/28/2018] [Accepted: 09/01/2018] [Indexed: 12/12/2022]
Abstract
Ovarian clear cell carcinoma (OCCC) is distinctive from other histological types of epithelial ovarian cancer, with genetic/epigenetic alterations, a specific immune-related molecular profile, and epidemiologic associations with ethnicity and endometriosis. These findings allow for the exploration of unique and specific treatments for OCCC. Two major mutated genes in OCCC are PIK3CA and ARID1A, which are frequently coexistent with each other. Other genes' alterations also contribute to activation of the PI3K (e.g. PIK3R1 and PTEN) and dysregulation of the chromatin remodeling complex (e.g. ARID1B, and SMARKA4). Although the number of focal copy number variations is small in OCCC, amplification is recurrently detected at chromosome 20q13.2 (including ZNF217), 8q, and 17q. Both expression and methylation profiling highlight the significance of adjustments to oxidative stress and inflammation. In particular, up-regulation of HNF-1β resulting from hypomethylation contributes to the switch from anaerobic to aerobic glucose metabolism. Additionally, up-regulation of HNF-1β activates STAT3 and NF-κB signaling, and leads to immune suppression via production of IL-6 and IL-8. Immune suppression may also be induced by the increased expression of PD-1, Tim-3 and LAG3. Mismatch repair deficient (microsatellite instable) tumors as found in Lynch syndrome also induce immune suppression in some OCCC. In a recent phase II clinical trial in heavily-treated platinum-resistant ovarian cancer, two out of twenty cases with a complete response to the anti-PD-1 antibody, nivolumab, were OCCC subtypes. Thus, the immune-suppressive state resulting from both genetic alterations and the unique tumor microenvironment may be associated with sensitivity to immune checkpoint inhibitors in OCCC. In this review, we highlight recent update and progress in OCCC from both the genomic and immunologic points of view, addressing the future candidate therapeutic options.
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Affiliation(s)
- Katsutoshi Oda
- Department of Obstetrics and Gynecology, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan.
| | - Junzo Hamanishi
- Department of Obstetrics and Gynecology, Kyoto University Graduate School of Medicine, Kyoto, Japan.
| | - Koji Matsuo
- Division of Gynecologic Oncology, Department of Obstetrics and Gynecology, University of Southern California, Los Angeles, CA, USA; Norris Comprehensive Cancer Center, University of Southern California, Los Angeles, CA, USA
| | - Kosei Hasegawa
- Department of Gynecologic Oncology, Saitama Medical University International Medical Center, Saitama, Japan
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Hazama S, Tamada K, Yamaguchi Y, Kawakami Y, Nagano H. Current status of immunotherapy against gastrointestinal cancers and its biomarkers: Perspective for precision immunotherapy. Ann Gastroenterol Surg 2018; 2:289-303. [PMID: 30003192 PMCID: PMC6036392 DOI: 10.1002/ags3.12180] [Citation(s) in RCA: 28] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/18/2018] [Accepted: 05/21/2018] [Indexed: 12/14/2022] Open
Abstract
Immunotherapy has shown encouraging results for some types of tumor. Although enormous efforts have been made toward the development of specific immunotherapeutic strategies against gastrointestinal cancers, such as adoptive T-cell transfer, peptide vaccines, or dendritic cell vaccines, the efficacy of immunotherapies prior to the introduction of immune checkpoint inhibitors was not substantial. This article reviews immunotherapy for gastrointestinal malignancies, including cell therapy, peptide vaccine, and immune checkpoint inhibitors, and attempts to resolve the immunosuppressive conditions surrounding the tumor microenvironment, and to construct novel combination immunotherapies beyond immune checkpoint inhibitors.
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Affiliation(s)
- Shoichi Hazama
- Department of Translational Research and Developmental Therapeutics against CancerYamaguchi University School of MedicineUbeJapan
| | - Koji Tamada
- Department of ImmunologyYamaguchi University Graduate School of MedicineUbeJapan
| | | | - Yutaka Kawakami
- Division of Cellular SignalingInstitute for Advanced Medical ResearchKeio University School of MedicineTokyoJapan
| | - Hiroaki Nagano
- Department of Gastroenterological, Breast and Endocrine SurgeryYamaguchi University Graduate School of MedicineUbeJapan
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Abouelghar A, Hasnah R, Taouk G, Saad M, Karam M. Prognostic values of the mRNA expression of natural killer receptor ligands and their association with clinicopathological features in breast cancer patients. Oncotarget 2018; 9:27171-27196. [PMID: 29930758 PMCID: PMC6007477 DOI: 10.18632/oncotarget.25506] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/12/2018] [Accepted: 05/14/2018] [Indexed: 12/31/2022] Open
Abstract
BACKGROUND Natural killer (NK) cells are lymphocytes of the innate immune system that have potent cytotoxic activity against tumor cells. NK cell recognition and activity towards cancer cells are regulated by an integrated interplay between numerous inhibitory and activating receptors acting in concert to eliminate tumor cells expressing cognate ligands. Despite strong evidence supporting the role of NK cells in breast cancer (BC) control, BC still develops and progresses to form large tumors and metastases. A major mechanism of BC escape from NK immunity is the alteration of the expression of NK receptor ligands. The aim of this study was to determine whether NK receptor ligands' mRNA expression might influence prognosis in BC patients and whether these effects differ by molecular subtypes and clinicopathological features. METHODS We used the KM plotter platform to analyze the correlation between mRNA expression of 32 NK receptor ligands and relapse-free survival (RFS) and overall survival (OS) in 3951 and 1402 BC patients, respectively. The association with tumor subtypes and clinicopathological features was determined. BC samples were split into high and low expression groups according to the best cutoff value and the two patient cohorts were compared by Kaplan-Meier survival plots. The hazard ratios with 95% confidence intervals and log rank P values were calculated and FDR-adjusted for multiple testing correction. The data was considered to be statistically significant when FDR-adjusted P value < 0.05. RESULTS High mRNA expression of around 80% of ligands for NK activating and inhibitory receptors associated with better RFS, which correlated with longer OS for only about half of the NK-activating ligands but for most NK-inhibitory ligands. Also, five NK-activating ligands correlated with worse prognosis. These prognostic values were differentially associated with the BC clinical criteria. In addition, the favorable prognostic influence of NK-activating ligands' upregulation, as a whole, was mainly significantly associated with HER2-positive and basal-like subtypes, lymph node positive phenotype, and high-grade tumors. CONCLUSIONS NK receptor ligands appear to play an important role in defining BC patient prognosis. Identification of a group of patients with worse prognosis expressing high levels of NK-activating ligands and low levels of NK-inhibitory ligands makes them ideal potential candidates for NK-based immunotherapy to eliminate residual tumor cells, prevent relapse and improve patient survival.
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Affiliation(s)
- Ali Abouelghar
- Cancer Research Center, Qatar Biomedical Research Institute, Hamad Bin Khalifa University, Qatar Foundation, Doha, Qatar
| | - Reem Hasnah
- Department of Biological Sciences, Carnegie Mellon University in Qatar, Doha, Qatar
| | - Ghina Taouk
- Cancer Research Center, Qatar Biomedical Research Institute, Hamad Bin Khalifa University, Qatar Foundation, Doha, Qatar
| | - Mohamad Saad
- Qatar Computing Research Institute, Hamad Bin Khalifa University, Doha, Qatar
| | - Manale Karam
- Cancer Research Center, Qatar Biomedical Research Institute, Hamad Bin Khalifa University, Qatar Foundation, Doha, Qatar
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Kawakami Y. Introduction: Cancer Immunology Special Issue-Immunopathology. Int Immunol 2018; 28:371. [PMID: 27450690 DOI: 10.1093/intimm/dxw033] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/14/2022] Open
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Nakamura K, Yaguchi T, Ohmura G, Kobayashi A, Kawamura N, Iwata T, Kiniwa Y, Okuyama R, Kawakami Y. Involvement of local renin-angiotensin system in immunosuppression of tumor microenvironment. Cancer Sci 2017; 109:54-64. [PMID: 29034589 PMCID: PMC5765296 DOI: 10.1111/cas.13423] [Citation(s) in RCA: 57] [Impact Index Per Article: 7.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/01/2017] [Revised: 10/07/2017] [Accepted: 10/10/2017] [Indexed: 12/16/2022] Open
Abstract
To improve current cancer immunotherapies, strategies to modulate various immunosuppressive cells including myeloid derived suppressor cells (MDSC) which were shown to be negative factors in immune‐checkpoint blockade therapy, need to be developed. In the present study, we evaluated the role of the local renin‐angiotensin system (RAS) in the tumor immune‐microenvironment using murine models bearing tumor cell lines in which RAS was not involved in their proliferation and angiogenetic ability. Giving angiotensin II receptor blockers (ARB) to C57BL/6 mice bearing murine colon cancer cell line MC38 resulted in significant enhancement of tumor antigen gp70 specific T cells. ARB administration did not change the numbers of CD11b+ myeloid cells in tumors, but significantly reduced their T‐cell inhibitory ability along with decreased production of various immunosuppressive factors including interleukin (IL)‐6, IL‐10, vascular endothelial growth factor (VEGF), and arginase by CD11b+ cells in tumors. ARB also decreased expression of immunosuppressive factors such as chemokine ligand 12 and nitric oxide synthase 2 in cancer‐associated fibroblasts (CAF). Last, combination of ARB and anti‐programmed death‐ligand 1 (PD‐L1) antibodies resulted in significant augmentation of anti‐tumor effects in a CD8+ T cell‐dependent way. These results showed that RAS is involved in the generation of an immunosuppressive tumor microenvironment caused by myeloid cells and fibroblasts, other than the previously shown proliferative and angiogenetic properties of cancer cells and macrophages, and that ARB can transform the immunosuppressive properties of MDSC and CAF and could be used in combination with PD‐1/PD‐L1 immune‐checkpoint blockade therapy.
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Affiliation(s)
- Kenta Nakamura
- Division of Cellular Signaling, Institute for Advanced Medical Research, Keio University School of Medicine, Tokyo, Japan.,Department of Dermatology, Shinshu University School of Medicine, Nagano, Japan
| | - Tomonori Yaguchi
- Division of Cellular Signaling, Institute for Advanced Medical Research, Keio University School of Medicine, Tokyo, Japan
| | - Gaku Ohmura
- Division of Cellular Signaling, Institute for Advanced Medical Research, Keio University School of Medicine, Tokyo, Japan
| | - Asuka Kobayashi
- Division of Cellular Signaling, Institute for Advanced Medical Research, Keio University School of Medicine, Tokyo, Japan
| | - Naoshi Kawamura
- Division of Cellular Signaling, Institute for Advanced Medical Research, Keio University School of Medicine, Tokyo, Japan
| | - Takashi Iwata
- Division of Cellular Signaling, Institute for Advanced Medical Research, Keio University School of Medicine, Tokyo, Japan
| | - Yukiko Kiniwa
- Department of Dermatology, Shinshu University School of Medicine, Nagano, Japan
| | - Ryuhei Okuyama
- Department of Dermatology, Shinshu University School of Medicine, Nagano, Japan
| | - Yutaka Kawakami
- Division of Cellular Signaling, Institute for Advanced Medical Research, Keio University School of Medicine, Tokyo, Japan
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Network-pharmacology-based validation of TAMS/CXCL-1 as key mediator of XIAOPI formula preventing breast cancer development and metastasis. Sci Rep 2017; 7:14513. [PMID: 29109519 PMCID: PMC5674025 DOI: 10.1038/s41598-017-15030-3] [Citation(s) in RCA: 44] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/20/2017] [Accepted: 10/19/2017] [Indexed: 12/16/2022] Open
Abstract
Network pharmacology has become a powerful means of understanding the mechanisms underlying the action of Chinese herbs in cancer treatment. This study aims to validate the preventive effects and molecular mechanisms of a clinical prescription XIAOPI formula against breast cancer. In vivo breast cancer xenograft data showed that XIAOPI delayed breast cancer development and efficiently inhibited lung metastasis, accompanied by prolonged survival benefits and decreased cancer stem cell subpopulations. However, similar phenomenon were not observed in a cell model. The herb-ingredient-target network analysis further identified a total of 81 genes closely correlated with the breast cancer chemoprevention effects of XIAOPI. Cytokine array analysis further validated CXCL-1 as the key target of XIAOPI both in vitro and in vivo. Evaluation of the mechanism demonstrated that CXCL-1 administration significantly abrogated the metastatic inhibition effects of XIAOPI on breast cancer migration, invasion, stem cells subpopulations, epithelial-mesenchymal transition(EMT), or mammosphere formation abilities. Overall, our study provides experimental evidence and molecular mechanisms that may facilitate the safe and effective use of herbal medicine for the prevention of breast cancer growth or metastasis, and may lead to CXCL-1-based therapeutic strategies for mammary malignancies.
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Janiak MK, Wincenciak M, Cheda A, Nowosielska EM, Calabrese EJ. Cancer immunotherapy: how low-level ionizing radiation can play a key role. Cancer Immunol Immunother 2017; 66:819-832. [PMID: 28361232 PMCID: PMC5489643 DOI: 10.1007/s00262-017-1993-z] [Citation(s) in RCA: 30] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/29/2016] [Accepted: 03/22/2017] [Indexed: 12/17/2022]
Abstract
The cancer immunoediting hypothesis assumes that the immune system guards the host against the incipient cancer, but also "edits" the immunogenicity of surviving neoplastic cells and supports remodeling of tumor microenvironment towards an immunosuppressive and pro-neoplastic state. Local irradiation of tumors during standard radiotherapy, by killing neoplastic cells and generating inflammation, stimulates anti-cancer immunity and/or partially reverses cancer-promoting immunosuppression. These effects are induced by moderate (0.1-2.0 Gy) or high (>2 Gy) doses of ionizing radiation which can also harm normal tissues, impede immune functions, and increase the risk of secondary neoplasms. In contrast, such complications do not occur with exposures to low doses (≤0.1 Gy for acute irradiation or ≤0.1 mGy/min dose rate for chronic exposures) of low-LET ionizing radiation. Furthermore, considerable evidence indicates that such low-level radiation (LLR) exposures retard the development of neoplasms in humans and experimental animals. Here, we review immunosuppressive mechanisms induced by growing tumors as well as immunomodulatory effects of LLR evidently or likely associated with cancer-inhibiting outcomes of such exposures. We also offer suggestions how LLR may restore and/or stimulate effective anti-tumor immunity during the more advanced stages of carcinogenesis. We postulate that, based on epidemiological and experimental data amassed over the last few decades, whole- or half-body irradiations with LLR should be systematically examined for its potential to be a viable immunotherapeutic treatment option for patients with systemic cancer.
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Affiliation(s)
- Marek K Janiak
- Department of Radiobiology and Radiation Protection, Military Institute of Hygiene and Epidemiology, 4 Kozielska St., 01-163, Warsaw, Poland.
| | - Marta Wincenciak
- Department of Radiobiology and Radiation Protection, Military Institute of Hygiene and Epidemiology, 4 Kozielska St., 01-163, Warsaw, Poland
| | - Aneta Cheda
- Department of Radiobiology and Radiation Protection, Military Institute of Hygiene and Epidemiology, 4 Kozielska St., 01-163, Warsaw, Poland
| | - Ewa M Nowosielska
- Department of Radiobiology and Radiation Protection, Military Institute of Hygiene and Epidemiology, 4 Kozielska St., 01-163, Warsaw, Poland
| | - Edward J Calabrese
- Department of Environmental Health Sciences, School of Public Health and Health Sciences, Morrill I, N344, University of Massachusetts, Amherst, MA, 01003, USA
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MYC: Master Regulator of Immune Privilege. Trends Immunol 2017; 38:298-305. [PMID: 28233639 DOI: 10.1016/j.it.2017.01.002] [Citation(s) in RCA: 70] [Impact Index Per Article: 8.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/03/2016] [Revised: 01/13/2017] [Accepted: 01/17/2017] [Indexed: 12/23/2022]
Abstract
Cancers are often initiated by genetic events that activate proto-oncogenes or inactivate tumor-suppressor genes. These events are also crucial for sustained tumor cell proliferation and survival, a phenomenon described as oncogene addiction. In addition to this cell-intrinsic role, recent evidence indicates that oncogenes also directly regulate immune responses, leading to immunosuppression. Expression of many oncogenes or loss of tumor suppressors induces the expression of immune checkpoints that regulate the immune response, such as PD-L1. We discuss here how oncogenes, and in particular MYC, suppress immune surveillance, and how oncogene-targeted therapies may restore the immune response against tumors.
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