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1
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Xu Q, Chu J, Hu Q, Sun Y, Jiang F, Li S, Liu L. The role and clinical significance of tumor-draining lymph nodes in tumor progression and immunotherapy. Crit Rev Oncol Hematol 2025; 212:104745. [PMID: 40315968 DOI: 10.1016/j.critrevonc.2025.104745] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/18/2025] [Revised: 04/12/2025] [Accepted: 04/23/2025] [Indexed: 05/04/2025] Open
Abstract
Tumor-draining lymph nodes (TDLNs) play a pivotal role in tumor growth and the immune response, activating immune cells such as CD8 + T cells and natural killer cells to combat tumors. However, tumors can subvert TDLNs to avoid immune attack. Initially, TDLNs stimulate a robust antitumor response, but as tumor evolve, they infiltrate with immunosuppressive cells that alter the TDLN environment and potentially promote metastasis. Immunotherapy, including immune checkpoint inhibitor (ICI), have emerged as a potential solution to this challenge by reconfiguring the TDLN environment to enhance immune responses and influence the immune status of the primary tumor. The integrity of the TDLNs is crucial for the efficacy of immunotherapy. Conventional surgery often removes TDLNs, but this may impede immune system function and the effectiveness of immunotherapy. It is therefore recommended that removal of TDLNs be considered after neoadjuvant treatment rather than before adjuvant treatment. Accurate identification of patients who require post-neoadjuvant TDLN removal and the determination of metastatic nodes is of paramount importance in tailoring treatment plans, optimizing of patient outcomes, and improving quality of life.
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Affiliation(s)
- Qian Xu
- Department of Medical Oncology, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan, Shandong 250012, China
| | - Jiahui Chu
- Department of Pharmacy, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan, Shandong 250012, China
| | - Qinqin Hu
- Department of Medical Oncology, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan, Shandong 250012, China
| | - Yanheng Sun
- Department of Medical Oncology, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan, Shandong 250012, China
| | - Fan Jiang
- Department of Medical Oncology, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan, Shandong 250012, China
| | - Song Li
- Department of Medical Oncology, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan, Shandong 250012, China
| | - Lian Liu
- Department of Medical Oncology, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan, Shandong 250012, China.
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2
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Ligan C, Ma XH, Zhao SL, Zhao W. The regulatory role and mechanism of mast cells in tumor microenvironment. Am J Cancer Res 2024; 14:1-15. [PMID: 38323271 PMCID: PMC10839313] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/04/2023] [Accepted: 12/25/2023] [Indexed: 02/08/2024] Open
Abstract
Mast cells (MCs) have emerged as pivotal contributors to both the defensive immune response and immunomodulation. They also exhibit regulatory functions in modulating pathological processes across various allergic diseases. The impact of MC presence within tumor tissues has garnered considerable attention, yielding conflicting findings. While some studies propose that MCs within tumor tissues promote tumor initiation and progression, others advocate an opposing perspective. Notably, evidence emphasizes the dual role of MCs in cancer, both as promoters and suppressors, is crucial for optimizing cancer treatment strategies. These conflicting viewpoints have generated substantial controversy, underscoring the need for a comprehensive understanding of MC's role in tumor immune responses.
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Affiliation(s)
- Caryl Ligan
- General Clinical Research Center, Nanjing First Hospital, China Pharmaceutical UniversityNanjing, Jiangsu, China
| | - Xin-Hua Ma
- General Clinical Research Center, Nanjing First Hospital, China Pharmaceutical UniversityNanjing, Jiangsu, China
| | - Shu-Li Zhao
- General Clinical Research Center, Nanjing First Hospital, China Pharmaceutical UniversityNanjing, Jiangsu, China
| | - Wei Zhao
- Department of Pathology, Nanjing First Hospital, Nanjing Medical UniversityNanjing, Jiangsu, China
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Guidolin D, Tamma R, Annese T, Tortorella C, Ingravallo G, Gaudio F, Musto P, Specchia G, Ribatti D. Different patterns of mast cell distribution in B-cell non-Hodgkin lymphomas. Pathol Res Pract 2023; 248:154661. [PMID: 37406375 DOI: 10.1016/j.prp.2023.154661] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/23/2023] [Revised: 06/28/2023] [Accepted: 06/30/2023] [Indexed: 07/07/2023]
Abstract
Tumor growth, progression, and metastatic capability in non-Hodgkin lymphomas (NHLs) are influenced by different component of tumor microenvironment, including inflammatory cells. Among these latter, mast cells play a crucial role. The spatial distribution of mast cells inside the tumor stroma of different types of B-cell NHLs has not yet been investigated. The aim of this study is to analyze the pattern of distribution of mast cells in biopsy samples obtained from three different types of B-cell NHLs by utilizing an image analysis system and a mathematical model to allow a quantitative estimation to characterize their spatial distribution. As concerns the spatial distributions exhibited by mast cells in diffuse large B cell lymphoma (DLBCL), some clustering was detected in both activated B-like (ABC) and germinal center B-like (GBC) groups. In follicular lymphoma (FL), mast cell spatial distribution tends to uniformly fill the tissue space as far as the grade of the pathology increases. Finally, in marginal lymphoma tissue (MALT) lymphoma, mast cells maintain a significantly clustered spatial distribution, suggesting a lower tendency of the cells to fill the tissue space in this pathological condition. Overall, the data of this study confirm that the analysis of the spatial distribution of the tumor cells is of particular significance for the knowledge of the biological processes occurring in tumor stroma and for the development of parameters to characterize the morphologic organization of the cellular patterns in different types of tumors.
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Affiliation(s)
- Diego Guidolin
- Department of Neuroscience, Section of Anatomy, University of Padova, Padova, Italy
| | - Roberto Tamma
- Department of Translational Biomedicine and Neuroscience, University of Bari Medical School, Bari, Italy
| | - Tiziana Annese
- Department of Medicine and Surgery, University LUM "G. Degennaro", Casamassima, Ba, Italy
| | - Cinzia Tortorella
- Department of Neuroscience, Section of Anatomy, University of Padova, Padova, Italy
| | - Giuseppe Ingravallo
- Section of Pathology, Department of Precision and Regenerative Medicine and Ionian Area, University of Bari Medical School, Bari, Italy
| | - Francesco Gaudio
- Section of Hematology, Department of Precision and Regenerative Medicine and Ionian Area, "Aldo Moro" University of Bari Medical School, Bari, Italy
| | - Pellegrino Musto
- Section of Hematology, Department of Precision and Regenerative Medicine and Ionian Area, "Aldo Moro" University of Bari Medical School, Bari, Italy
| | - Giorgina Specchia
- Section of Hematology, Department of Precision and Regenerative Medicine and Ionian Area, "Aldo Moro" University of Bari Medical School, Bari, Italy
| | - Domenico Ribatti
- Department of Translational Biomedicine and Neuroscience, University of Bari Medical School, Bari, Italy.
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4
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Benito-Martin A, Nogués L, Hergueta-Redondo M, Castellano-Sanz E, Garvin E, Cioffi M, Sola-Castrillo P, Buehring W, Ximénez-Embún P, Muñoz J, Matei I, Villanueva J, Peinado H. Mast cells impair melanoma cell homing and metastasis by inhibiting HMGA1 secretion. Immunology 2023; 168:362-373. [PMID: 36352838 DOI: 10.1111/imm.13604] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/31/2022] [Accepted: 11/04/2022] [Indexed: 11/11/2022] Open
Abstract
Metastatic disease is the major cause of death from cancer. From the primary tumour, cells remotely prepare the environment of the future metastatic sites by secreted factors and extracellular vesicles. During this process, known as pre-metastatic niche formation, immune cells play a crucial role. Mast cells are haematopoietic bone marrow-derived innate immune cells whose function in lung immune response to invading tumours remains to be defined. We found reduced melanoma lung metastasis in mast cell-deficient mouse models (Wsh and MCTP5-Cre-RDTR), supporting a pro-metastatic role for mast cells in vivo. However, due to evidence pointing to their antitumorigenic role, we studied the impact of mast cells in melanoma cell function in vitro. Surprisingly, in vitro co-culture of bone-marrow-derived mast cells with melanoma cells showed that they have an intrinsic anti-metastatic activity. Mass spectrometry analysis of melanoma-mast cell co-cultures secretome showed that HMGA1 secretion by melanoma cells was significantly impaired. Consistently, HMGA1 knockdown in B16-F10 cells reduced their metastatic capacity in vivo. Importantly, analysis of HMGA1 expression in human melanoma tumours showed that metastatic tumours with high HMGA1 expression are associated with reduced overall and disease-free survival. Moreover, we show that HMGA1 is reduced in the nuclei and enriched in the cytoplasm of melanoma metastatic lesions when compared to primary tumours. These data suggest that high HMGA1 expression and secretion from melanoma cells promote metastatic behaviour. Targeting HMGA1 expression intrinsically or extrinsically by mast cells actions reduce melanoma metastasis. Our results pave the way to the use of HMGA1 as anti-metastatic target in melanoma as previously suggested in other cancer types.
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Affiliation(s)
- Alberto Benito-Martin
- Children's Cancer and Blood Foundation Laboratories, Departments of Pediatrics, and Cell and Developmental Biology, Drukier Institute for Children's Health and the Meyer Cancer Center, Weill Cornell Medical College, New York, New York, USA.,Universidad Alfonso X El Sabio, Facultad de Medicina, Unidad de Investigación Biomédica, Madrid, Spain
| | - Laura Nogués
- Children's Cancer and Blood Foundation Laboratories, Departments of Pediatrics, and Cell and Developmental Biology, Drukier Institute for Children's Health and the Meyer Cancer Center, Weill Cornell Medical College, New York, New York, USA.,Microenvironment and Metastasis Laboratory, Molecular Oncology Program, Spanish National Cancer Research Center (CNIO), Madrid, Spain
| | - Marta Hergueta-Redondo
- Microenvironment and Metastasis Laboratory, Molecular Oncology Program, Spanish National Cancer Research Center (CNIO), Madrid, Spain
| | - Elena Castellano-Sanz
- Microenvironment and Metastasis Laboratory, Molecular Oncology Program, Spanish National Cancer Research Center (CNIO), Madrid, Spain
| | - Eduardo Garvin
- Microenvironment and Metastasis Laboratory, Molecular Oncology Program, Spanish National Cancer Research Center (CNIO), Madrid, Spain
| | - Michele Cioffi
- Children's Cancer and Blood Foundation Laboratories, Departments of Pediatrics, and Cell and Developmental Biology, Drukier Institute for Children's Health and the Meyer Cancer Center, Weill Cornell Medical College, New York, New York, USA
| | - Paloma Sola-Castrillo
- Children's Cancer and Blood Foundation Laboratories, Departments of Pediatrics, and Cell and Developmental Biology, Drukier Institute for Children's Health and the Meyer Cancer Center, Weill Cornell Medical College, New York, New York, USA
| | - Weston Buehring
- Children's Cancer and Blood Foundation Laboratories, Departments of Pediatrics, and Cell and Developmental Biology, Drukier Institute for Children's Health and the Meyer Cancer Center, Weill Cornell Medical College, New York, New York, USA
| | - Pilar Ximénez-Embún
- Proteomics Unit-ProteoRed-ISCIII, Spanish National Cancer Research Centre (CNIO), Madrid, Spain
| | - Javier Muñoz
- Proteomics Unit-ProteoRed-ISCIII, Spanish National Cancer Research Centre (CNIO), Madrid, Spain
| | - Irina Matei
- Children's Cancer and Blood Foundation Laboratories, Departments of Pediatrics, and Cell and Developmental Biology, Drukier Institute for Children's Health and the Meyer Cancer Center, Weill Cornell Medical College, New York, New York, USA
| | | | - Héctor Peinado
- Microenvironment and Metastasis Laboratory, Molecular Oncology Program, Spanish National Cancer Research Center (CNIO), Madrid, Spain
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Hou Y, Wang Q, Su L, Zhu Y, Xiao Y, Feng F. Increased tumor-associated mast cells facilitate thyroid cancer progression by inhibiting CD8+ T cell function through galectin-9. Braz J Med Biol Res 2023; 56:e12370. [PMID: 37042867 PMCID: PMC10085758 DOI: 10.1590/1414-431x2023e12370] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/29/2022] [Accepted: 02/15/2023] [Indexed: 04/13/2023] Open
Abstract
As an important component of solid tumors, mast cells show specific phenotypes in various tumor microenvironments. However, the precise mechanism of mast cell accumulation and the phenotypic features of thyroid cancer (TC) remain largely unknown. Here, we found that mast cells were obviously recruited to tumor tissue by TC-derived stem cell factor (SCF). With tumor progression, mast cell levels increased gradually. In addition, intratumoral mast cells expressed higher levels of the immunosuppressive molecule galectin-9, which effectively suppresses CD8+ T-cell antitumor immunity in vitro. Blocking galectin-9 on tumor-infiltrating mast cells reversed the immunosuppression of CD8+ T cells. In conclusion, our data elucidated novel protumorigenic and immunosuppressive roles of mast cells in TC. In addition, our results indicated that blocking mast cells may impede tumor progression and ameliorate the prognosis of TC patients.
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Affiliation(s)
- Yanli Hou
- Department of Oncology and Hematology, Chongqing Hospital of Traditional Chinese Medicine, Chongqing, China
| | - Qiang Wang
- Department of Orthodontics, Deyang Stomatological Hospital, Deyang, Sichuan, China
| | - Li Su
- Department of Oncology and Hematology, Chongqing Hospital of Traditional Chinese Medicine, Chongqing, China
| | - Ying Zhu
- Department of Oncology and Hematology, Chongqing Hospital of Traditional Chinese Medicine, Chongqing, China
| | - Yun Xiao
- Department of Oncology and Hematology, Chongqing Hospital of Traditional Chinese Medicine, Chongqing, China
| | - Fei Feng
- Department of Oncology and Hematology, Chongqing Hospital of Traditional Chinese Medicine, Chongqing, China
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Luo Y, Zhang H, Yu J, Wei L, Li M, Xu W. Stem cell factor/mast cell/CCL2/monocyte/macrophage axis promotes Coxsackievirus B3 myocarditis and cardiac fibrosis by increasing Ly6C high monocyte influx and fibrogenic mediators production. Immunology 2022; 167:590-605. [PMID: 36054617 DOI: 10.1111/imm.13556] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/15/2021] [Accepted: 02/10/2022] [Indexed: 06/15/2023] Open
Abstract
Mast cells (MCs), central players in allergy and parasitic infections, play key roles in inflammation and fibrosis. Here, the impact of MCs on the progression of Coxsackievirus B3 (CVB3)-induced viral myocarditis (VMC) and fibrosis was investigated using MC-deficient KitW-sh mice. Viral titres, cellular infiltrates and heart pathologies were evaluated and compared with wild-type (WT) mice during acute CVB3 infection of C57BL/6 mice. CVB3 infection induced an increased accumulation and degranulation of MCs in the hearts of mice during acute infection. MC-deficient KitW-sh mice had slightly higher viral titres, decreased VMC and cardiac fibrosis and improved cardiac dysfunction compared to WT mice via decreasing cardiac influx of Ly6Chigh monocytes/macrophages (Mo/Mφ). While bone marrow-derived MC reconstitution decreased viral titre and worsened improved survival and VMC severity in Wsh mice. MC-fibroblasts co-culture revealed a cardiac MC-fibroblasts crosstalk during early infection: fibroblasts trigger MC degranulation and secretion of CCL2 and tumour necrosis factor alpha (TNF-α) via producing early stem cell factor (SCF); while MCs-fibrogenic mediators (TNF-α) stimulate fibroblasts to increase CCL2, α-smooth muscle actin (SMA), collagen and transforming growth factor beta（TGFβ) expression, thus aggravating cardiac fibrosis. MCs and fibroblast-derived CCL2s are both essential for cardiac Ly6Chigh Mo/Mφ influx. Administration of recombinant mouse SCF to CVB3-infected mice aggravates VMC via accelerating MCs accumulation and cardiac influx of Ly6Chi Mo/Mφ. Collectively, our data highlight an early MC-fibroblast crosstalk and SCF/MC/CCL2/Mo/Mφ axis as important mechanisms required for triggering VMC and myocardial fibrosis. This finding indicates critical roles of MCs in initiating and modulating cardiac innate response to CVB3 and has an implication in developing new and more effective treatments for VMC.
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Affiliation(s)
- Yuan Luo
- Jiangsu Provincial Key Laboratory of Infection and Immunity, Institutes of Biology and Medical Sciences, Soochow University, Suzhou, China
| | - Hongkai Zhang
- Jiangsu Provincial Key Laboratory of Infection and Immunity, Institutes of Biology and Medical Sciences, Soochow University, Suzhou, China
| | - Jie Yu
- Jiangsu Provincial Key Laboratory of Infection and Immunity, Institutes of Biology and Medical Sciences, Soochow University, Suzhou, China
| | - Lin Wei
- Jiangsu Provincial Key Laboratory of Infection and Immunity, Institutes of Biology and Medical Sciences, Soochow University, Suzhou, China
| | - Min Li
- Jiangsu Provincial Key Laboratory of Infection and Immunity, Institutes of Biology and Medical Sciences, Soochow University, Suzhou, China
| | - Wei Xu
- Jiangsu Provincial Key Laboratory of Infection and Immunity, Institutes of Biology and Medical Sciences, Soochow University, Suzhou, China
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Zheng JH, Yao HF, Duan ZH, Ji PX, Yang J, Zhu YH, Jia QY, Yang JY, Liu DJ, Sun YW, Chen PC, Shi PD, Chen L. Exploitation and Verification of a Stroma- and Metastasis-Associated Risk Prognostic Signature in Pancreatic Adenocarcinoma. Pharmaceuticals (Basel) 2022; 15:1336. [PMID: 36355508 PMCID: PMC9696859 DOI: 10.3390/ph15111336] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/14/2022] [Revised: 10/25/2022] [Accepted: 10/26/2022] [Indexed: 09/10/2024] Open
Abstract
Pancreatic adenocarcinoma (PAAD), one of the most malignant tumors, not only has abundant mesenchymal components, but is also characterized by an extremely high metastatic risk. The purpose of this study was to construct a model of stroma- and metastasis-associated prognostic signature, aiming to benefit the existing clinical staging system and predict the prognosis of patients. First, stroma-associated genes were screened from the TCGA database with the ESTIMATE algorithm. Subsequently, transcriptomic data from clinical tissues in the RenJi cohort were screened for metastasis-associated genes. Integrating the two sets of genes, we constructed a risk prognostic signature by Cox and LASSO regression analysis. We then obtained a risk score by a quantitative formula and divided all samples into high- and low-risk groups based on the scores. The results demonstrated that patients with high-risk scores have a worse prognosis than those with low-risk scores, both in the TCGA database and in the RenJi cohort. In addition, tumor mutation burden, chemotherapeutic drug sensitivity and immune infiltration analysis also exhibited significant differences between the two groups. In exploring the potential mechanisms of how stromal components affect tumor metastasis, we simulated different matrix stiffness in vitro to explore its effect on EMT key genes in PAAD cells. We found that cancer cells stimulated by high matrix stiffness may trigger EMT and promote PAAD metastasis.
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Affiliation(s)
- Jia-Hao Zheng
- State Key Laboratory of Oncogenes and Related Genes, Department of Biliary-Pancreatic Surgery, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 200127, China
| | - Hong-Fei Yao
- State Key Laboratory of Oncogenes and Related Genes, Department of Biliary-Pancreatic Surgery, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 200127, China
| | - Zong-Hao Duan
- State Key Laboratory of Oncogenes and Related Genes, Department of Biliary-Pancreatic Surgery, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 200127, China
| | - Pei-Xuan Ji
- Shanghai Institute of Digestive Disease, Division of Gastroenterology and Hepatology, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 200001, China
| | - Jian Yang
- State Key Laboratory of Oncogenes and Related Genes, Department of Biliary-Pancreatic Surgery, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 200127, China
| | - Yu-Heng Zhu
- State Key Laboratory of Oncogenes and Related Genes, Department of Biliary-Pancreatic Surgery, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 200127, China
| | - Qin-Yuan Jia
- State Key Laboratory of Oncogenes and Related Genes, Department of Biliary-Pancreatic Surgery, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 200127, China
| | - Jian-Yu Yang
- State Key Laboratory of Oncogenes and Related Genes, Department of Biliary-Pancreatic Surgery, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 200127, China
| | - De-Jun Liu
- State Key Laboratory of Oncogenes and Related Genes, Department of Biliary-Pancreatic Surgery, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 200127, China
| | - Yong-Wei Sun
- State Key Laboratory of Oncogenes and Related Genes, Department of Biliary-Pancreatic Surgery, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 200127, China
| | - Peng-Cheng Chen
- Department of General Surgery, Jiading District Central Hospital Affiliated Shanghai University of Medicine & Health Sciences, Shanghai 201800, China
| | - Pei-Dong Shi
- Department of General Surgery, Jiading District Central Hospital Affiliated Shanghai University of Medicine & Health Sciences, Shanghai 201800, China
| | - Li Chen
- State Key Laboratory of Oncogenes and Related Genes, Department of Biliary-Pancreatic Surgery, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 200127, China
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Sheikh E, Tran T, Vranic S, Levy A, Bonfil RD. Role and significance of c-KIT receptor tyrosine kinase in cancer: A review. Bosn J Basic Med Sci 2022; 22:683-698. [PMID: 35490363 PMCID: PMC9519160 DOI: 10.17305/bjbms.2021.7399] [Citation(s) in RCA: 12] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/20/2022] [Accepted: 04/21/2022] [Indexed: 11/16/2022] Open
Abstract
c-kit is a classical proto-oncogene that encodes a receptor tyrosine kinase (RTK) that responds to stem cell factor (SCF). C-KIT signaling is a critical regulator of cell proliferation, survival, and migration and is implicated in several physiological processes, including pigmentation, hematopoiesis and gut movement. Accumulating evidence suggests that dysregulated c-KIT function, caused by either overexpression or mutations in c-kit, promotes tumor development and progression in various human cancers. In this review, we discuss the most important structural and biological features of c-KIT, as well as insights into the activation of intracellular signaling pathways following SCF binding to this RTK. We then illustrate how different c-kit alterations are associated with specific human cancers and describe recent studies that highlight the contribution of c-KIT to cancer stemness, epithelial-mesenchymal transition and progression to metastatic disease in different experimental models. The impact of tyrosine kinase inhibitors in treating c-KIT-positive tumors and limitations due to their propensity to develop drug resistance are summarized. Finally, we appraise the potential of novel therapeutic approaches targeting c-KIT more selectively while minimizing toxicity to normal tissue.
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Affiliation(s)
- Emana Sheikh
- OMS-III, Dr. Kiran C. Patel College of Osteopathic Medicine, Nova Southeastern University, Fort Lauderdale, Florida, United States
| | - Tony Tran
- OMS-III, Dr. Kiran C. Patel College of Osteopathic Medicine, Nova Southeastern University, Fort Lauderdale, Florida, United States
| | - Semir Vranic
- Department of Basic Medical Sciences, College of Medicine, QU Health, Qatar University, Doha, Qatar
| | - Arkene Levy
- Department of Medical Education, Dr. Kiran C. Patel College of Allopathic Medicine, Nova Southeastern University, Fort Lauderdale, Florida, United States
| | - R. Daniel Bonfil
- Department of Medical Education, Dr. Kiran C. Patel College of Allopathic Medicine, Nova Southeastern University, Fort Lauderdale, Florida, United States
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Cheng Y, Tang R, Li X, Wang B, Cheng Y, Xiao S, Sun P, Yu W, Li C, Lin X, Zhu Y. LRP1B is a Potential Biomarker for Tumor Immunogenicity and Prognosis of HCC Patients Receiving ICI Treatment. J Hepatocell Carcinoma 2022; 9:203-220. [PMID: 35345553 PMCID: PMC8957351 DOI: 10.2147/jhc.s348785] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/11/2021] [Accepted: 03/05/2022] [Indexed: 12/11/2022] Open
Abstract
Background New predictors of the efficacy of hepatocellular carcinoma (HCC) immunotherapy are needed. The ability of a single gene mutation to predict the therapeutic effect of immune checkpoint inhibitors (ICI) in HCC remains unknown. Methods The most frequently mutated genes in HCC were analyzed using the Cancer Genome Atlas (TCGA) and International Cancer Genome Consortium (ICGC) datasets. Mutant genes that correlated with the tumor mutational burden (TMB) and prognosis were obtained. The mutation pattern and immunological function of one of the most frequently mutated genes, LRP1B, were determined. A pan-tumor analysis of LRP1B expression, association with cancer prognosis, and immunological role was also explored. A retrospective clinical study was conducted using 102 HCC patients who received ICI treatment to further verify whether gene mutations can predict the effectiveness of immunotherapy and prognosis of HCC. Results LRP1B is among the most frequently mutated genes in HCC cohorts in TCGA and ICGC datasets. TCGA data showed that the LRP1B mutation activated immune signaling pathways and promoted mast cell activation. Patients with LRP1B mutations had significantly higher TMB than those with wild-type LRP1B. LRP1B expression correlated with the cancer-immunity cycle and immune cell infiltration. High LRP1B expression was also associated with poor survival among HCC patients. Results from the clinical study showed that HCC patients in the LRP1B mutation group had a poor response to ICI and worse prognosis than the wild-type group. The LRP1B mutation group had significantly higher TMB and mast cell infiltration in tumor tissues. Conclusion This study is the first to report that a single gene LRP1B mutation is associated with a poor clinical response to ICI treatment and negative outcomes in HCC patients. HighLRP1B expression correlated with tumor immunity and HCC prognosis.
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Affiliation(s)
- Yang Cheng
- Digestive Department, Guangzhou Women and Children’s Medical Center, Guangzhou Medical University, Guangzhou, Guangdong, People’s Republic of China
- Liver Tumor Center, Department of Infectious Diseases and Hepatology Unit, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong, People’s Republic of China
| | - Rui Tang
- Digestive Department, Guangzhou Women and Children’s Medical Center, Guangzhou Medical University, Guangzhou, Guangdong, People’s Republic of China
| | - Xiangzhao Li
- Department of Pathology, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong, People’s Republic of China
| | - Biao Wang
- Department of Hepatobiliary Surgery, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong, People’s Republic of China
| | - Yanling Cheng
- Digestive Department, Guangzhou Women and Children’s Medical Center, Guangzhou Medical University, Guangzhou, Guangdong, People’s Republic of China
| | - Shuzhe Xiao
- Digestive Department, Guangzhou Women and Children’s Medical Center, Guangzhou Medical University, Guangzhou, Guangdong, People’s Republic of China
| | - Penghui Sun
- Nanfang PET Center, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong, People’s Republic of China
| | - Wenxuan Yu
- Liver Tumor Center, Department of Infectious Diseases and Hepatology Unit, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong, People’s Republic of China
| | - Cheng Li
- Liver Tumor Center, Department of Infectious Diseases and Hepatology Unit, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong, People’s Republic of China
| | - Xinsheng Lin
- Liver Tumor Center, Department of Infectious Diseases and Hepatology Unit, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong, People’s Republic of China
| | - Yun Zhu
- Liver Tumor Center, Department of Infectious Diseases and Hepatology Unit, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong, People’s Republic of China
- Correspondence: Yun Zhu, Liver Tumor Center, Department of Infectious Diseases and Hepatology Unit, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong, 510515, People’s Republic of China, Email
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Mast Cell–Tumor Interactions: Molecular Mechanisms of Recruitment, Intratumoral Communication and Potential Therapeutic Targets for Tumor Growth. Cells 2022; 11:cells11030349. [PMID: 35159157 PMCID: PMC8834237 DOI: 10.3390/cells11030349] [Citation(s) in RCA: 28] [Impact Index Per Article: 9.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/18/2021] [Revised: 01/08/2022] [Accepted: 01/13/2022] [Indexed: 12/13/2022] Open
Abstract
Mast cells (MCs) are tissue-resident immune cells that are important players in diseases associated with chronic inflammation such as cancer. Since MCs can infiltrate solid tumors and promote or limit tumor growth, a possible polarization of MCs to pro-tumoral or anti-tumoral phenotypes has been proposed and remains as a challenging research field. Here, we review the recent evidence regarding the complex relationship between MCs and tumor cells. In particular, we consider: (1) the multifaceted role of MCs on tumor growth suggested by histological analysis of tumor biopsies and studies performed in MC-deficient animal models; (2) the signaling pathways triggered by tumor-derived chemotactic mediators and bioactive lipids that promote MC migration and modulate their function inside tumors; (3) the possible phenotypic changes on MCs triggered by prevalent conditions in the tumor microenvironment (TME) such as hypoxia; (4) the signaling pathways that specifically lead to the production of angiogenic factors, mainly VEGF; and (5) the possible role of MCs on tumor fibrosis and metastasis. Finally, we discuss the novel literature on the molecular mechanisms potentially related to phenotypic changes that MCs undergo into the TME and some therapeutic strategies targeting MC activation to limit tumor growth.
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11
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Tumor-Associated Mast Cells in Urothelial Bladder Cancer: Optimizing Immuno-Oncology. Biomedicines 2021; 9:biomedicines9111500. [PMID: 34829729 PMCID: PMC8614912 DOI: 10.3390/biomedicines9111500] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/20/2021] [Revised: 10/14/2021] [Accepted: 10/16/2021] [Indexed: 12/28/2022] Open
Abstract
Urothelial bladder cancer (UBC) is one of the most prevalent and aggressive malignancies. Recent evidence indicates that the tumor microenvironment (TME), including a variety of immune cells, is a critical modulator of tumor initiation, progression, evolution, and treatment resistance. Mast cells (MCs) in UBC are possibly involved in tumor angiogenesis, tissue remodeling, and immunomodulation. Moreover, tumor-infiltration by MCs has been reported in early-stage UBC patients. This infiltration is linked with a favorable or unfavorable prognosis depending on the tumor type and location. Despite the discrepancy of MC function in tumor progression, MCs can modify the TME to regulate the immunity and infiltration of tumors by producing an array of mediators. Nonetheless, the precise role of MCs in UBC tumor progression and evolution remains unknown. Thus, this review discusses some critical roles of MCs in UBC. Patients with UBC are treated at both early and late stages by immunotherapeutic methods, including intravenous bacillus Calmette–Guérin instillation and immune checkpoint blockade. An understanding of the patient response and resistance mechanisms in UBC is required to unlock the complete potential of immunotherapy. Since MCs are pivotal to understand the underlying processes and predictors of therapeutic responses in UBC, our review also focuses on possible immunotherapeutic treatments that involve MCs.
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12
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Lichterman JN, Reddy SM. Mast Cells: A New Frontier for Cancer Immunotherapy. Cells 2021; 10:cells10061270. [PMID: 34063789 PMCID: PMC8223777 DOI: 10.3390/cells10061270] [Citation(s) in RCA: 72] [Impact Index Per Article: 18.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/18/2021] [Revised: 05/13/2021] [Accepted: 05/19/2021] [Indexed: 12/24/2022] Open
Abstract
Mast cells are unique tissue-resident immune cells of the myeloid lineage that have long been implicated in the pathogenesis of allergic and autoimmune disorders. More recently, mast cells have been recognized as key orchestrators of anti-tumor immunity, modulators of the cancer stroma, and have also been implicated in cancer cell intrinsic properties. As such, mast cells are an underrecognized but very promising target for cancer immunotherapy. In this review, we discuss the role of mast cells in shaping cancer and its microenvironment, the interaction between mast cells and cancer therapies, and strategies to target mast cells to improve cancer outcomes. Specifically, we address (1) decreasing cell numbers through c-KIT inhibition, (2) modulating mast cell activation and phenotype (through mast cell stabilizers, FcεR1 signaling pathway activators/inhibitors, antibodies targeting inhibitory receptors and ligands, toll like receptor agonists), and (3) altering secreted mast cell mediators and their downstream effects. Finally, we discuss the importance of translational research using patient samples to advance the field of mast cell targeting to optimally improve patient outcomes. As we aim to expand the successes of existing cancer immunotherapies, focused clinical and translational studies targeting mast cells in different cancer contexts are now warranted.
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Affiliation(s)
- Jake N. Lichterman
- Division of Hematology/Oncology, Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA;
| | - Sangeetha M. Reddy
- Division of Hematology/Oncology, Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA;
- Harold C. Simmons Comprehensive Cancer Center, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA
- Correspondence: ; Tel.: +1-214-648-4180
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13
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Gaissmaier L, Christopoulos P. Immune Modulation in Lung Cancer: Current Concepts and Future Strategies. Respiration 2020; 99:1-27. [PMID: 33291116 DOI: 10.1159/000510385] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/20/2020] [Accepted: 07/10/2020] [Indexed: 12/24/2022] Open
Abstract
Cancer immunotherapy represents the most dynamic field of biomedical research currently, with thoracic immuno-oncology as a forerunner. PD-(L)1 inhibitors are already part of standard first-line treatment for both non-small-cell and small-cell lung cancer, while unprecedented 5-year survival rates of 15-25% have been achieved in pretreated patients with metastatic disease. Evolving strategies are mainly aiming for improvement of T-cell function, increase of immune activation in the tumor microenvironment (TME), and supply of tumor-reactive lymphocytes. Several novel therapeutics have demonstrated preclinical efficacy and are increasingly used in rational combinations within clinical trials. Two overarching trends dominate: extension of immunotherapy to earlier disease stages, mainly as neoadjuvant treatment, and a shift of focus towards multivalent, individualized, mutatome-based antigen-specific modalities, mainly adoptive cell therapies and cancer vaccines. The former ensures ample availability of treated and untreated patient samples, the latter facilitates deeper mechanistic insights, and both in combination build an overwhelming force that is accelerating progress and driving the greatest revolution cancer medicine has seen so far. Today, immune modulation represents the most potent therapeutic modality in oncology, the most important topic in clinical and translational cancer research, and arguably our greatest, meanwhile justified hope for achieving cure of pulmonary neoplasms and other malignancies in the next future.
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Affiliation(s)
- Lena Gaissmaier
- Department of Thoracic Oncology, Thoraxklinik at Heidelberg University Hospital, Heidelberg, Germany
- Translational Lung Research Center Heidelberg (TLRC-H), German Center for Lung Research (DZL), Heidelberg, Germany
| | - Petros Christopoulos
- Department of Thoracic Oncology, Thoraxklinik at Heidelberg University Hospital, Heidelberg, Germany,
- Translational Lung Research Center Heidelberg (TLRC-H), German Center for Lung Research (DZL), Heidelberg, Germany,
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14
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Bao X, Shi R, Zhao T, Wang Y. Mast cell-based molecular subtypes and signature associated with clinical outcome in early-stage lung adenocarcinoma. Mol Oncol 2020; 14:917-932. [PMID: 32175651 PMCID: PMC7191192 DOI: 10.1002/1878-0261.12670] [Citation(s) in RCA: 38] [Impact Index Per Article: 7.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/28/2019] [Revised: 01/28/2020] [Accepted: 03/12/2020] [Indexed: 12/27/2022] Open
Abstract
Mast cells are a major component of the immune microenvironment in tumour tissues and modulate tumour progression by releasing pro‐tumorigenic and antitumorigenic molecules. Regarding the impact of mast cells on the outcomes of patients with lung adenocarcinoma (LUAD) patient, several published studies have shown contradictory results. Here, we aimed at elucidating the role of mast cells in early‐stage LUAD. We found that high mast cell abundance was correlated with prolonged survival in early‐stage LUAD patients. The mast cell‐related gene signature and gene mutation data sets were used to stratify early‐stage LUAD patients into two molecular subtypes (subtype 1 and subtype 2). The neural network‐based framework constructed with the mast cell‐related signature showed high accuracy in predicting response to immunotherapy. Importantly, the prognostic mast cell‐related signature predicted the survival probability and the potential relationship between TP53 mutation, c‐MYC activation and mast cell activities. The meta‐analysis confirmed the prognostic value of the mast cell‐related gene signature. In summary, this study might improve our understanding of the role of mast cells in early‐stage LUAD and aid in the development of immunotherapy and personalized treatments for early‐stage LUAD patients.
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Affiliation(s)
- Xuanwen Bao
- Institute of Radiation Biology, Helmholtz Center Munich, German Research Center for Environmental Health, Neuherberg, Germany.,Technical University Munich (TUM), Germany
| | - Run Shi
- Department of Radiation Oncology, University Hospital, Ludwig Maximilian University of Munich, Germany
| | - Tianyu Zhao
- Institute and Clinic for Occupational, Social and Environmental Medicine, University Hospital, Ludwig Maximilian University of Munich, Germany.,Comprehensive Pneumology Center (CPC) Munich, Member DZL, Germany.,German Center for Lung Research, Munich, Germany.,Institute of Epidemiology, Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg, Germany
| | - Yanfang Wang
- Ludwig-Maximilians-Universität München (LMU), Munich, Germany
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15
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Olivera A, Rivera J. Paradigm Shifts in Mast Cell and Basophil Biology and Function: An Emerging View of Immune Regulation in Health and Disease. Methods Mol Biol 2020; 2163:3-31. [PMID: 32766962 DOI: 10.1007/978-1-0716-0696-4_1] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 05/20/2023]
Abstract
The physiological role of the mast cell and basophil has for many years remained enigmatic. In this chapter, we briefly summarize some of the more recent studies that shed new light on the role of mast cells and basophils in health and disease. What we gain from these studies is a new appreciation for mast cells and basophils as sentinels in host defense and a further understanding that dysregulation of mast cell and basophil function can be a component of various diseases other than allergies. Perhaps the most important insight reaped from this work is the increasing awareness that mast cells and basophils can function as immunoregulatory cells that modulate the immune response in health and disease. Collectively, the recent knowledge provides new challenges and opportunities toward the development of novel therapeutic strategies to augment host protection and modify disease through manipulation of mast cell and basophil function.
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Affiliation(s)
- Ana Olivera
- Molecular Immunology Section, Laboratory of Molecular Immunogenetics, National Institute of Arthritis and Musculoskeletal and Skin Diseases, National Institutes of Health, Bethesda, MD, USA.
- Mast Cell Biology Section, Laboratory of Allergic Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health (NIH), Bethesda, MD, USA.
| | - Juan Rivera
- Molecular Immunology Section, Laboratory of Molecular Immunogenetics, National Institute of Arthritis and Musculoskeletal and Skin Diseases, National Institutes of Health, Bethesda, MD, USA
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16
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Mast cells drive IgE-mediated disease but might be bystanders in many other inflammatory and neoplastic conditions. J Allergy Clin Immunol 2019; 144:S19-S30. [DOI: 10.1016/j.jaci.2019.07.017] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/03/2018] [Revised: 06/11/2019] [Accepted: 07/08/2019] [Indexed: 01/05/2023]
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17
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Reddy SM, Reuben A, Barua S, Jiang H, Zhang S, Wang L, Gopalakrishnan V, Hudgens CW, Tetzlaff MT, Reuben JM, Tsujikawa T, Coussens LM, Wani K, He Y, Villareal L, Wood A, Rao A, Woodward WA, Ueno NT, Krishnamurthy S, Wargo JA, Mittendorf EA. Poor Response to Neoadjuvant Chemotherapy Correlates with Mast Cell Infiltration in Inflammatory Breast Cancer. Cancer Immunol Res 2019; 7:1025-1035. [PMID: 31043414 DOI: 10.1158/2326-6066.cir-18-0619] [Citation(s) in RCA: 77] [Impact Index Per Article: 12.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/05/2018] [Revised: 12/18/2018] [Accepted: 04/22/2019] [Indexed: 12/28/2022]
Abstract
Our understanding is limited concerning the tumor immune microenvironment of inflammatory breast cancer (IBC), an aggressive form of primary cancer with low rates of pathologic complete response to current neoadjuvant chemotherapy (NAC) regimens. We retrospectively identified pretreatment (N = 86) and matched posttreatment tissue (N = 27) from patients with stage III or de novo stage IV IBC who received NAC followed by a mastectomy. Immune profiling was performed including quantification of lymphoid and myeloid infiltrates by IHC and T-cell repertoire analysis. Thirty-four of 86 cases in this cohort (39.5%) achieved a pathologic complete response. Characterization of the tumor microenvironment revealed that having a lower pretreatment mast cell density was significantly associated with achieving a pathologic complete response to NAC (P = 0.004), with responders also having more stromal tumor-infiltrating lymphocytes (P = 0.035), CD8+ T cells (P = 0.047), and CD20+ B cells (P = 0.054). Spatial analysis showed close proximity of mast cells to CD8+ T cells, CD163+ monocytes/macrophages, and tumor cells when pathologic complete response was not achieved. PD-L1 positivity on tumor cells was found in fewer than 2% of cases and on immune cells in 27% of cases, but with no correlation to response. Our results highlight the strong association of mast cell infiltration with poor response to NAC, suggesting a mechanism of treatment resistance and a potential therapeutic target in IBC. Proximity of mast cells to immune and tumor cells may suggest immunosuppressive or tumor-promoting interactions of these mast cells.
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Affiliation(s)
- Sangeetha M Reddy
- Department of Breast Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas.,Department of Internal Medicine, The University of Texas Southwestern Medical Center, Dallas, Texas
| | - Alexandre Reuben
- Department of Surgical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas.,Department of Thoracic/Head and Neck Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas
| | - Souptik Barua
- Department of Electrical and Computer Engineering, Rice University, Houston, Texas.,Department of Computational Medicine and Bioinformatics, University of Michigan, Ann Arbor, Michigan
| | - Hong Jiang
- Department of Surgical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas
| | - Shaojun Zhang
- Department of Genomic Medicine, The University of Texas MD Anderson Cancer Center, Houston, Texas
| | - Linghua Wang
- Department of Genomic Medicine, The University of Texas MD Anderson Cancer Center, Houston, Texas
| | | | - Courtney W Hudgens
- Department of Translational Molecular Pathology, The University of Texas MD Anderson Cancer Center, Houston, Texas
| | - Michael T Tetzlaff
- Department of Translational Molecular Pathology, The University of Texas MD Anderson Cancer Center, Houston, Texas.,Department of Pathology, The University of Texas MD Anderson Cancer Center, Houston, Texas
| | - James M Reuben
- Department of Hematopathology, The University of Texas MD Anderson Cancer Center, Houston, Texas.,Morgan Welch Inflammatory Breast Cancer Research Program and Clinic, Houston, Texas
| | - Takahiro Tsujikawa
- Department of Cell, Developmental, and Cancer Biology, Oregon Health and Science University, Portland, Oregon.,Department of Otolaryngology-Head and Neck Surgery, Kyoto Prefectural University of Medicine, Kyoto, Japan
| | - Lisa M Coussens
- Department of Cell, Developmental, and Cancer Biology, Oregon Health and Science University, Portland, Oregon
| | - Khalida Wani
- Department of Translational Molecular Pathology, The University of Texas MD Anderson Cancer Center, Houston, Texas
| | - Yan He
- Department of Translational Molecular Pathology, The University of Texas MD Anderson Cancer Center, Houston, Texas
| | - Lily Villareal
- Morgan Welch Inflammatory Breast Cancer Research Program and Clinic, Houston, Texas
| | - Anita Wood
- Morgan Welch Inflammatory Breast Cancer Research Program and Clinic, Houston, Texas
| | - Arvind Rao
- Department of Computational Medicine and Bioinformatics, University of Michigan, Ann Arbor, Michigan.,Department of Radiation Oncology, University of Michigan, Ann Arbor, Michigan
| | - Wendy A Woodward
- Morgan Welch Inflammatory Breast Cancer Research Program and Clinic, Houston, Texas.,Department of Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas
| | - Naoto T Ueno
- Department of Breast Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas. .,Morgan Welch Inflammatory Breast Cancer Research Program and Clinic, Houston, Texas
| | - Savitri Krishnamurthy
- Morgan Welch Inflammatory Breast Cancer Research Program and Clinic, Houston, Texas. .,Department of Breast Surgical Pathology, The University of Texas MD Anderson Cancer Center, Houston, Texas
| | - Jennifer A Wargo
- Department of Surgical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas. .,Department of Genomic Medicine, The University of Texas MD Anderson Cancer Center, Houston, Texas
| | - Elizabeth A Mittendorf
- Department of Breast Surgical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas. .,Division of Breast Surgery, Department of Surgery, Brigham and Women's Hospital, Boston, Massachusetts.,Breast Oncology Program, Dana-Farber/Brigham and Women's Cancer Center, Boston, Massachusetts
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18
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Ghouse SM, Polikarpova A, Muhandes L, Dudeck J, Tantcheva-Poór I, Hartmann K, Lesche M, Dahl A, Eming S, Müller W, Behrendt R, Roers A. Although Abundant in Tumor Tissue, Mast Cells Have No Effect on Immunological Micro-milieu or Growth of HPV-Induced or Transplanted Tumors. Cell Rep 2019; 22:27-35. [PMID: 29298428 DOI: 10.1016/j.celrep.2017.12.010] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/01/2017] [Revised: 09/27/2017] [Accepted: 12/04/2017] [Indexed: 02/09/2023] Open
Abstract
High numbers of mast cells populate the stroma of many types of neoplasms, including human papilloma virus-induced benign and malignant tumors in man and mouse. Equipped with numerous pattern recognition receptors and capable of executing important pro-inflammatory responses, mast cells are considered innate sentinels that significantly impact tumor biology. Mast cells were reported to promote human papilloma virus (HPV)-induced epithelial hyperproliferation and neo-angiogenesis in an HPV-driven mouse model of skin cancer. We analyzed HPV-induced epithelial hyperplasia and squamous cell carcinoma formation, as well as growth of tumors inoculated into the dermis, in mice lacking skin mast cells. Unexpectedly, the absence of mast cells had no effect on HPV-induced epithelial growth or angiogenesis, on growth kinetics of inoculated tumors, or on the immunological tumor micro-milieu. Thus, the conspicuous recruitment of mast cells into tumor tissues cannot necessarily be equated with important mast cell functions in tumor growth.
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Affiliation(s)
| | - Anastasia Polikarpova
- Institute for Immunology, Medical Faculty Carl Gustav Carus, TU Dresden, 01307 Dresden, Germany
| | - Lina Muhandes
- Institute for Immunology, Medical Faculty Carl Gustav Carus, TU Dresden, 01307 Dresden, Germany
| | - Jan Dudeck
- Institute for Immunology, Medical Faculty Carl Gustav Carus, TU Dresden, 01307 Dresden, Germany
| | | | - Karin Hartmann
- Department of Dermatology, University of Luebeck, 23538 Luebeck, Germany
| | | | - Andreas Dahl
- Biotechnology Center, TU Dresden, 01307 Dresden, Germany
| | - Sabine Eming
- Department of Dermatology, University of Cologne, 50931 Cologne, Germany
| | - Werner Müller
- Faculty of Biology, Medicine and Health, University of Manchester, Manchester M13 9PT, UK
| | - Rayk Behrendt
- Institute for Immunology, Medical Faculty Carl Gustav Carus, TU Dresden, 01307 Dresden, Germany
| | - Axel Roers
- Institute for Immunology, Medical Faculty Carl Gustav Carus, TU Dresden, 01307 Dresden, Germany.
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19
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Yamazaki A, Kobayashi K, Murata T. [The roles of mast cells in tumor microenvironment]. Nihon Yakurigaku Zasshi 2018; 152:160-162. [PMID: 30185734 DOI: 10.1254/fpj.152.160] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/28/2022]
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20
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Liu Z, Zhu Y, Xu L, Zhang J, Xie H, Fu H, Zhou Q, Chang Y, Dai B, Xu J. Tumor stroma-infiltrating mast cells predict prognosis and adjuvant chemotherapeutic benefits in patients with muscle invasive bladder cancer. Oncoimmunology 2018; 7:e1474317. [PMID: 30393586 DOI: 10.1080/2162402x.2018.1474317] [Citation(s) in RCA: 60] [Impact Index Per Article: 8.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/15/2017] [Revised: 04/25/2018] [Accepted: 05/03/2018] [Indexed: 01/14/2023] Open
Abstract
Which subgroups patients with muscle-invasive bladder cancer (MIBC) could benefit most from adjuvant chemotherapy (ACT) is blurred. Here we tried to stratify MIBC patients with tumor infiltrating mast cells (TIMs), explore the prognostic and predictive value of TIMs, and provide possible cellular explanations. We selected 259 MIBC patients who underwent radical cystectomy from two independent clinical centers between 2002 and 2014. TIMs were evaluated and prognostic and predictive value was assessed. The CIBERSORT method, Gene Set Enrichment Analysis (GSEA) and differential gene expression analyses were performed to explore the possible cellular mechanisms. TIMs infiltration was distinct between stromal and epithelial area of MIBC specimens. Patients with higher stromal TIMs had a significant worse overall survival and recurrence free survival (HR = 2.228, 95%CI: 1.467-3.550; P = 0.001 and HR = 1.984, 95%CI: 1.105-3.374; P = 0.016). More importantly, pT2 patients with low stromal TIMs tended to have a lower risk of death and recurrence after ACT (HR = 0.233, 95%CI: 0.020-0.814; P = 0.033 and HR = 0.180, 95%CI: 0.022-0.722; P = 0.031). A negative correlativity between TIMs and CD8 + T cells was identified on TCGA-BLCA cohort. Immunohistochemistry results validated that high stromal TIMs were negatively correlated with CD8 + T cells (Spearman's rho = -0.215, P < 0.001). Differential gene expression suggested that low TIMs might represent a state of immune activation in MIBC. To conclude, high stromal TIMs infiltration was an independent unfavorable prognosticator for MIBC patients. Patients with low stromal TIMs might benefit the most from ACT, especially in pT2 stage.
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Affiliation(s)
- Zheng Liu
- Department of Urology, Fudan University Shanghai Cancer Center, Shanghai, China.,Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China
| | - Yu Zhu
- Department of Urology, Fudan University Shanghai Cancer Center, Shanghai, China.,Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China
| | - Le Xu
- Department of Urology, Ruijin Hospital, School of Medicine, Shanghai Jiaotong University, Shanghai, China
| | - Junyu Zhang
- Department of Urology, Fudan University Shanghai Cancer Center, Shanghai, China.,Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China
| | - Huyang Xie
- Department of Urology, Fudan University Shanghai Cancer Center, Shanghai, China.,Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China
| | - Hangcheng Fu
- Department of Urology, Fudan University Shanghai Cancer Center, Shanghai, China.,Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China
| | - Quan Zhou
- Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Fudan University, Shanghai, China
| | - Yuan Chang
- Department of Urology, Fudan University Shanghai Cancer Center, Shanghai, China.,Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China
| | - Bo Dai
- Department of Urology, Fudan University Shanghai Cancer Center, Shanghai, China.,Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China
| | - Jiejie Xu
- Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Fudan University, Shanghai, China
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21
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MacDonald F, Zaiss DMW. The Immune System's Contribution to the Clinical Efficacy of EGFR Antagonist Treatment. Front Pharmacol 2017; 8:575. [PMID: 28970798 PMCID: PMC5609556 DOI: 10.3389/fphar.2017.00575] [Citation(s) in RCA: 31] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/28/2017] [Accepted: 08/10/2017] [Indexed: 12/17/2022] Open
Abstract
Epidermal Growth Factor Receptor (EGFR) antagonists were one of the first anti-cancer treatments developed targeting a Receptor Tyrosine Kinase. However, the underlying mode of action of how EGFR antagonist application can explain its clinical efficacy in different types of cancers remains largely unresolved. Numerous findings have suggested that a substantial portion of the effects attributed to EGFR antagonist treatment might not be based on direct influence on the tumor itself. Instead it may be based on indirect effects, potentially mediated via the immune system. In this review the role of the EGFR for the functioning of the immune system is discussed, alongside how EGFR antagonist treatment could be impacting tumor growth by blocking macrophage and FoxP3-expressing regulatory CD4+ T cell function. Based on these findings, we consider implications for current treatment schemes and suggest novel approaches to improve the efficacy of EGFR antagonist treatment in the future. Finally, we propose potential ways to improve EGFR antagonists, in order to enhance their clinical efficacy whilst diminishing unwanted side effects.
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Affiliation(s)
- Felicity MacDonald
- School of Biological Sciences, Institute of Immunology and Infection Research, University of EdinburghEdinburgh, United Kingdom
| | - Dietmar M W Zaiss
- School of Biological Sciences, Institute of Immunology and Infection Research, University of EdinburghEdinburgh, United Kingdom
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22
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Stahl M, Gedrich R, Peck R, LaVallee T, Eder JP. Targeting KIT on innate immune cells to enhance the antitumor activity of checkpoint inhibitors. Immunotherapy 2017; 8:767-74. [PMID: 27349976 DOI: 10.2217/imt-2016-0040] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/02/2023] Open
Abstract
Innate immune cells such as mast cells and myeloid-derived suppressor cells are key components of the tumor microenvironment. Recent evidence indicates that levels of myeloid-derived suppressor cells in melanoma patients are associated with poor survival to checkpoint inhibitors. This suggests that targeting both the innate and adaptive suppressive components of the immune system will maximize clinical benefit and elicit more durable responses in cancer patients. Preclinical data suggest that targeting signaling by the receptor tyrosine kinase KIT, particularly on mast cells, may modulate innate immune cell numbers and activity in tumors. Here, we review data highlighting the importance of the KIT signaling in regulating antitumor immune responses and the potential benefit of combining selective KIT inhibitors with immune checkpoint inhibitors.
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Affiliation(s)
- Maximilian Stahl
- Department of Internal Medicine, Yale School of Medicine, 333 Cedar Street, New Haven, CT, USA
| | - Richard Gedrich
- Kolltan Pharmaceuticals, 300 George Street Suite 530, New Haven, CT, USA
| | - Ronald Peck
- Kolltan Pharmaceuticals, 300 George Street Suite 530, New Haven, CT, USA
| | - Theresa LaVallee
- Kolltan Pharmaceuticals, 300 George Street Suite 530, New Haven, CT, USA
| | - Joseph Paul Eder
- Department of Medical Oncology & Yale Cancer Center, Yale School of Medicine, 333 Cedar Street, WWW211, New Haven, CT 06520, USA
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23
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Varricchi G, Galdiero MR, Loffredo S, Marone G, Iannone R, Marone G, Granata F. Are Mast Cells MASTers in Cancer? Front Immunol 2017; 8:424. [PMID: 28446910 PMCID: PMC5388770 DOI: 10.3389/fimmu.2017.00424] [Citation(s) in RCA: 235] [Impact Index Per Article: 29.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/15/2017] [Accepted: 03/27/2017] [Indexed: 12/19/2022] Open
Abstract
Prolonged low-grade inflammation or smoldering inflammation is a hallmark of cancer. Mast cells form a heterogeneous population of immune cells with differences in their ultra-structure, morphology, mediator content, and surface receptors. Mast cells are widely distributed throughout all tissues and are stromal components of the inflammatory microenvironment that modulates tumor initiation and development. Although canonically associated with allergic disorders, mast cells are a major source of pro-tumorigenic (e.g., angiogenic and lymphangiogenic factors) and antitumorigenic molecules (e.g., TNF-α and IL-9), depending on the milieu. In certain neoplasias (e.g., gastric, thyroid and Hodgkin's lymphoma) mast cells play a pro-tumorigenic role, in others (e.g., breast cancer) a protective role, whereas in yet others they are apparently innocent bystanders. These seemingly conflicting results suggest that the role of mast cells and their mediators could be cancer specific. The microlocalization (e.g., peritumoral vs intratumoral) of mast cells is another important aspect in the initiation/progression of solid and hematologic tumors. Increasing evidence in certain experimental models indicates that targeting mast cells and/or their mediators represent a potential therapeutic target in cancer. Thus, mast cells deserve focused consideration also as therapeutic targets in different types of tumors. There are many unanswered questions that should be addressed before we understand whether mast cells are an ally, adversary, or innocent bystanders in human cancers.
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Affiliation(s)
- Gilda Varricchi
- Department of Translational Medical Sciences (DiSMeT), Center for Basic and Clinical Immunology Research (CISI), University of Naples Federico II, Naples, Italy
| | - Maria Rosaria Galdiero
- Department of Translational Medical Sciences (DiSMeT), Center for Basic and Clinical Immunology Research (CISI), University of Naples Federico II, Naples, Italy
| | - Stefania Loffredo
- Department of Translational Medical Sciences (DiSMeT), Center for Basic and Clinical Immunology Research (CISI), University of Naples Federico II, Naples, Italy
| | - Giancarlo Marone
- Department of Public Health, University of Naples Federico II, Monaldi Hospital Pharmacy, Naples, Italy
| | - Raffaella Iannone
- Department of Translational Medical Sciences (DiSMeT), Center for Basic and Clinical Immunology Research (CISI), University of Naples Federico II, Naples, Italy
| | - Gianni Marone
- Department of Translational Medical Sciences (DiSMeT), Center for Basic and Clinical Immunology Research (CISI), University of Naples Federico II, Naples, Italy
- Institute of Experimental Endocrinology and Oncology “Gaetano Salvatore” (IEOS), National Research Council (CNR), Naples, Italy
| | - Francescopaolo Granata
- Department of Translational Medical Sciences (DiSMeT), Center for Basic and Clinical Immunology Research (CISI), University of Naples Federico II, Naples, Italy
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Chen X, Liu L, Wang Y, Liu B, Zeng D, Jin Q, Li M, Zhang D, Liu Q, Xie H. Identification of breast cancer recurrence risk factors based on functional pathways in tumor and normal tissues. Oncotarget 2017; 8:20679-20694. [PMID: 27564264 PMCID: PMC5400536 DOI: 10.18632/oncotarget.11557] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/30/2015] [Accepted: 07/26/2016] [Indexed: 01/05/2023] Open
Abstract
The recurrence of breast cancer (BC) is a serious therapeutic problem, and the risk factors for recurrence urgently need to be identified. In this study, we examined the functional pathways in tumor and normal tissues to more comprehensively identify biomarkers for the risk of BC recurrence. We collected tumor and normal tissue gene expression profiles of recurrent BC patients and non-recurrent BC patients from the TCGA database.We derived an expression interval (mean ± 1.96SD) based on non-recurrent patients rather than a single value, such as a mean or median. If the expression of a gene was significantly different from its normal expression interval, it was considered a differentially expressed gene. Eight pathways that significantly distinguished recurrent and non-recurrent BC patients were obtained based on 65% accuracy, and these pathways were all associated with the immune response and sensitivity to drugs. The genes in these eight pathways were also used to analyze survival, and the significance level reached 0.003 in an independent dataset (p = 0.02 in tumor and p = 0.03 in normal tissue). Our results reveal that the integration of tumor and normal tissue functional analyses can comprehensively enhance the understanding of BC prognosis.
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Affiliation(s)
- Xiujie Chen
- College of Bioinformatics Science and Technology, Harbin Medical University, Harbin, Heilongjiang, 150081, PR China
| | - Lei Liu
- College of Bioinformatics Science and Technology, Harbin Medical University, Harbin, Heilongjiang, 150081, PR China
| | - YunFeng Wang
- College of Bioinformatics Science and Technology, Harbin Medical University, Harbin, Heilongjiang, 150081, PR China
| | - Bo Liu
- College of Bioinformatics Science and Technology, Harbin Medical University, Harbin, Heilongjiang, 150081, PR China
| | - Diheng Zeng
- College of Bioinformatics Science and Technology, Harbin Medical University, Harbin, Heilongjiang, 150081, PR China
| | - Qing Jin
- College of Bioinformatics Science and Technology, Harbin Medical University, Harbin, Heilongjiang, 150081, PR China
| | - MengJian Li
- College of Bioinformatics Science and Technology, Harbin Medical University, Harbin, Heilongjiang, 150081, PR China
| | - DeNan Zhang
- College of Bioinformatics Science and Technology, Harbin Medical University, Harbin, Heilongjiang, 150081, PR China
| | - Qiuqi Liu
- College of Bioinformatics Science and Technology, Harbin Medical University, Harbin, Heilongjiang, 150081, PR China
| | - Hongbo Xie
- College of Bioinformatics Science and Technology, Harbin Medical University, Harbin, Heilongjiang, 150081, PR China
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Garton AJ, Seibel S, Lopresti-Morrow L, Crew L, Janson N, Mandiyan S, Trombetta ES, Pankratz S, LaVallee TM, Gedrich R. Anti-KIT Monoclonal Antibody Treatment Enhances the Antitumor Activity of Immune Checkpoint Inhibitors by Reversing Tumor-Induced Immunosuppression. Mol Cancer Ther 2017; 16:671-680. [DOI: 10.1158/1535-7163.mct-16-0676] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/13/2016] [Revised: 12/15/2016] [Accepted: 12/16/2016] [Indexed: 11/16/2022]
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Young JS, Daniels MD, Miller ML, Wang T, Zhong R, Yin D, Alegre ML, Chong AS. Erosion of Transplantation Tolerance After Infection. Am J Transplant 2017; 17:81-90. [PMID: 27273890 PMCID: PMC5938732 DOI: 10.1111/ajt.13910] [Citation(s) in RCA: 23] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/26/2016] [Revised: 06/01/2016] [Accepted: 06/03/2016] [Indexed: 01/25/2023]
Abstract
Recent clinical studies suggest that operational allograft tolerance can be persistent, but long-term surviving allografts can be rejected in a subset of patients, sometimes after episodes of infection. In this study, we examined the impact of Listeria monocytogenes (Lm) infection on the quality of tolerance in a mouse model of heart allograft transplantation. Lm infection induced full rejection in 40% of tolerant recipients, with the remaining experiencing a rejection crisis or no palpable change in their allografts. In the surviving allografts on day 8 postinfection, graft-infiltrating cell numbers increased and exhibited a loss in the tolerance gene signature. By day 30 postinfection, the tolerance signature was broadly restored, but with a discernible reduction in the expression of a subset of 234 genes that marked tolerance and was down-regulated at day 8 post-Lm infection. We further demonstrated that the tolerant state after Lm infection was functionally eroded, as rejection of the long-term surviving graft was induced with anti-PD-L1 whereas the same treatment had no effect in noninfected tolerant mice. Collectively, these observations demonstrate that tolerance, even if initially robust, exists as a continuum that can be eroded following bystander immune responses that accompany certain infections.
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Affiliation(s)
- James S Young
- Section of Transplantation, Department of Surgery, Chicago State University, Chicago, IL 60628
| | - Melvin D Daniels
- Section of Transplantation, Department of Surgery, Chicago State University, Chicago, IL 60628
- Department of Biological Sciences, Chicago State University, Chicago, IL 60628
| | - Michelle L Miller
- Section of Rheumatology, Department of Medicine, Chicago State University, Chicago, IL 60628
| | - Tongmin Wang
- Section of Transplantation, Department of Surgery, Chicago State University, Chicago, IL 60628
| | - Rong Zhong
- Section of Transplantation, Department of Surgery, Chicago State University, Chicago, IL 60628
| | - Dengping Yin
- Section of Transplantation, Department of Surgery, Chicago State University, Chicago, IL 60628
| | - Maria-Luisa Alegre
- Section of Rheumatology, Department of Medicine, Chicago State University, Chicago, IL 60628
| | - Anita S. Chong
- Section of Transplantation, Department of Surgery, Chicago State University, Chicago, IL 60628
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AID/APOBEC-network reconstruction identifies pathways associated with survival in ovarian cancer. BMC Genomics 2016; 17:643. [PMID: 27527602 PMCID: PMC4986275 DOI: 10.1186/s12864-016-3001-y] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/17/2015] [Accepted: 08/08/2016] [Indexed: 01/03/2023] Open
Abstract
BACKGROUND Building up of pathway-/disease-relevant signatures provides a persuasive tool for understanding the functional relevance of gene alterations and gene network associations in multifactorial human diseases. Ovarian cancer is a highly complex heterogeneous malignancy in respect of tumor anatomy, tumor microenvironment including pro-/antitumor immunity and inflammation; still, it is generally treated as single disease. Thus, further approaches to investigate novel aspects of ovarian cancer pathogenesis aiming to provide a personalized strategy to clinical decision making are of high priority. Herein we assessed the contribution of the AID/APOBEC family and their associated genes given the remarkable ability of AID and APOBECs to edit DNA/RNA, and as such, providing tools for genetic and epigenetic alterations potentially leading to reprogramming of tumor cells, stroma and immune cells. RESULTS We structured the study by three consecutive analytical modules, which include the multigene-based expression profiling in a cohort of patients with primary serous ovarian cancer using a self-created AID/APOBEC-associated gene signature, building up of multivariable survival models with high predictive accuracy and nomination of top-ranked candidate/target genes according to their prognostic impact, and systems biology-based reconstruction of the AID/APOBEC-driven disease-relevant mechanisms using transcriptomics data from ovarian cancer samples. We demonstrated that inclusion of the AID/APOBEC signature-based variables significantly improves the clinicopathological variables-based survival prognostication allowing significant patient stratification. Furthermore, several of the profiling-derived variables such as ID3, PTPRC/CD45, AID, APOBEC3G, and ID2 exceed the prognostic impact of some clinicopathological variables. We next extended the signature-/modeling-based knowledge by extracting top genes co-regulated with target molecules in ovarian cancer tissues and dissected potential networks/pathways/regulators contributing to pathomechanisms. We thereby revealed that the AID/APOBEC-related network in ovarian cancer is particularly associated with remodeling/fibrotic pathways, altered immune response, and autoimmune disorders with inflammatory background. CONCLUSIONS The herein study is, to our knowledge, the first one linking expression of entire AID/APOBECs and interacting genes with clinical outcome with respect to survival of cancer patients. Overall, data propose a novel AID/APOBEC-derived survival model for patient risk assessment and reconstitute mapping to molecular pathways. The established study algorithm can be applied further for any biologically relevant signature and any type of diseased tissue.
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Roeser JC, Leach SD, McAllister F. Emerging strategies for cancer immunoprevention. Oncogene 2015; 34:6029-39. [PMID: 26364615 PMCID: PMC11073473 DOI: 10.1038/onc.2015.98] [Citation(s) in RCA: 30] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/08/2015] [Revised: 02/25/2015] [Accepted: 02/27/2015] [Indexed: 12/13/2022]
Abstract
The crucial role of the immune system in the formation and progression of tumors has been widely accepted. On one hand, the surveillance role of the immune system plays an important role in endogenous tumor prevention, but on the other hand, in some special circumstances such as in chronic inflammation, the immune system can actually contribute to the formation and progression of tumors. In recent years, there has been an explosion of novel targeted immunotherapies for advanced cancers. In the present manuscript, we explore known and potential various types of cancer prevention strategies and focus on nonvaccine-based cancer preventive strategies targeting the immune system at the early stages of tumorigenesis.
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Affiliation(s)
| | - Steven D. Leach
- The David M. Rubenstein Center for Pancreatic Cancer Research, Memorial Sloan Kettering Cancer Center, New York, NY
| | - Florencia McAllister
- Department of Clinical Cancer Prevention. The University of Texas MD Anderson Cancer Center. Houston, TX
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29
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Paradigm shifts in mast cell and basophil biology and function: an emerging view of immune regulation in health and disease. Methods Mol Biol 2015; 1192:3-31. [PMID: 25149480 DOI: 10.1007/978-1-4939-1173-8_1] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
The physiological role of the mast cell and basophil has for many years remained enigmatic. In this chapter we briefly summarize some of the more recent studies that shed new light on the role of mast cells and basophils in health and disease. What we gain from these studies is a new appreciation for mast cells and basophils as sentinels in host defense and a further understanding that dysregulation of mast cell and basophil function can be a component of various diseases other than allergies. Perhaps, the most important insight reaped from this work is the increasing awareness that mast cells and basophils can function as immunoregulatory cells that modulate the immune response in health and disease. Collectively, the recent knowledge provides new challenges and opportunities towards the development of novel therapeutic strategies to augment host protection and modify disease through manipulation of mast cell and basophil function.
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30
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Marichal T, Tsai M, Galli SJ. Mast cells: potential positive and negative roles in tumor biology. Cancer Immunol Res 2015; 1:269-79. [PMID: 24777963 DOI: 10.1158/2326-6066.cir-13-0119] [Citation(s) in RCA: 130] [Impact Index Per Article: 13.0] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022]
Abstract
Mast cells are immune cells that reside in virtually all vascularized tissues. Upon activation by diverse mechanisms, mast cells can secrete a broad array of biologically active products that either are stored in the cytoplasmic granules of the cells (e.g., histamine, heparin, various proteases) or are produced de novo upon cell stimulation (e.g., prostaglandins, leukotrienes, cytokines, chemokines, and growth factors). Mast cells are best known for their effector functions during anaphylaxis and acute IgE-associated allergic reactions, but they also have been implicated in a wide variety of processes that maintain health or contribute to disease. There has been particular interest in the possible roles of mast cells in tumor biology. In vitro studies have shown that mast cells have the potential to influence many aspects of tumor biology, including tumor development, tumor-induced angiogenesis, and tissue remodeling, and the shaping of adaptive immune responses to tumors. Yet, the actual contributions of mast cells to tumor biology in vivo remain controversial. Here, we review some basic features of mast cell biology with a special emphasis on those relevant to their potential roles in tumors. We discuss how using in vivo tumor models in combination with models in which mast cell function can be modulated has implicated mast cells in the regulation of host responses to tumors. Finally, we summarize data from studies of human tumors that suggest either beneficial or detrimental roles for mast cells in tumors.
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Affiliation(s)
- Thomas Marichal
- Authors' Affiliations: Departments of Microbiology and Immunology, Stanford University School of Medicine, Stanford, California
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31
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Visciano C, Liotti F, Prevete N, Cali' G, Franco R, Collina F, de Paulis A, Marone G, Santoro M, Melillo RM. Mast cells induce epithelial-to-mesenchymal transition and stem cell features in human thyroid cancer cells through an IL-8-Akt-Slug pathway. Oncogene 2015; 34:5175-86. [PMID: 25619830 DOI: 10.1038/onc.2014.441] [Citation(s) in RCA: 177] [Impact Index Per Article: 17.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/20/2014] [Revised: 11/21/2014] [Accepted: 12/16/2014] [Indexed: 12/18/2022]
Abstract
There is increasing evidence that mast cells (MCs) and their mediators are involved in the remodeling of the tumor microenvironment and promote tumor growth, angiogenesis and metastasis. We have found that an increased density of MCs in thyroid cancer (TC) correlates with enhanced invasiveness. However, the MC-derived factors responsible for this activity and the mechanisms by which they enhance TC invasiveness remain unidentified. Here, we report that MCs, when activated by TC cells, produce soluble factors that induce epithelial-to-mesenchymal transition (EMT) and stemness features of TC cells. We identified CXCL8/interleukin (IL)-8 as the main mediator contained in activated MC conditioned media (CM) capable of inducing both EMT and stemness of TC cells. Mechanistically, MC CM or exogenous IL-8 stimulated Akt phosphorylation and Slug expression in TC cells. The inhibition of the Akt pathway or depletion of the Slug transcription factor by RNA interference, reverted EMT and stemness responses. TC cells stably transfected with exogenous IL-8 underwent EMT, displayed increased stemness and enhanced tumorigenicity with respect to control cells. The analysis of TC surgical specimens by immunohistochemical analysis demonstrated a positive correlation between MC density (Tryptase(+) cells) and stemness features (OCT4 staining). Taken together, our data identify an MC-dependent IL-8-Akt-Slug pathway that sustains EMT/stemness of TC cells. The blockade of this circuit might be exploited for the therapy of advanced TC.
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Affiliation(s)
- C Visciano
- Dipartimento di Medicina Molecolare e Biotecnologie Mediche/Istituto di Endocrinologia ed Oncologia Sperimentale del CNR 'G. Salvatore', University of Naples Federico II, Naples, Italy
| | - F Liotti
- Dipartimento di Medicina Molecolare e Biotecnologie Mediche/Istituto di Endocrinologia ed Oncologia Sperimentale del CNR 'G. Salvatore', University of Naples Federico II, Naples, Italy
| | - N Prevete
- Dipartimento di Scienze Mediche Traslazionali/Centro Interdipartimentale di Ricerca in Scienze Immunologiche di Base e Cliniche, University of Naples Federico II, Naples, Italy
| | - G Cali'
- Dipartimento di Medicina Molecolare e Biotecnologie Mediche/Istituto di Endocrinologia ed Oncologia Sperimentale del CNR 'G. Salvatore', University of Naples Federico II, Naples, Italy
| | - R Franco
- Struttura Complessa di Anatomia Patologica, Istituto Nazionale Tumori, Fondazione G. Pascale, Naples, Italy
| | - F Collina
- Struttura Complessa di Anatomia Patologica, Istituto Nazionale Tumori, Fondazione G. Pascale, Naples, Italy
| | - A de Paulis
- Dipartimento di Scienze Mediche Traslazionali/Centro Interdipartimentale di Ricerca in Scienze Immunologiche di Base e Cliniche, University of Naples Federico II, Naples, Italy
| | - G Marone
- Dipartimento di Scienze Mediche Traslazionali/Centro Interdipartimentale di Ricerca in Scienze Immunologiche di Base e Cliniche, University of Naples Federico II, Naples, Italy
| | - M Santoro
- Dipartimento di Medicina Molecolare e Biotecnologie Mediche/Istituto di Endocrinologia ed Oncologia Sperimentale del CNR 'G. Salvatore', University of Naples Federico II, Naples, Italy
| | - R M Melillo
- Dipartimento di Medicina Molecolare e Biotecnologie Mediche/Istituto di Endocrinologia ed Oncologia Sperimentale del CNR 'G. Salvatore', University of Naples Federico II, Naples, Italy
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Groot Kormelink T, Powe DG, Kuijpers SA, Abudukelimu A, Fens MHAM, Pieters EHE, Kassing van der Ven WW, Habashy HO, Ellis IO, Blokhuis BR, Thio M, Hennink WE, Storm G, Redegeld FA, Schiffelers RM. Immunoglobulin free light chains are biomarkers of poor prognosis in basal-like breast cancer and are potential targets in tumor-associated inflammation. Oncotarget 2015; 5:3159-67. [PMID: 24931643 PMCID: PMC4102799 DOI: 10.18632/oncotarget.1868] [Citation(s) in RCA: 29] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/16/2022] Open
Abstract
Inflammation is an important component of various cancers and its inflammatory cells and mediators have been shown to have prognostic potential. Tumor-infiltrating mast cells can promote tumor growth and angiogenesis, but the mechanism of mast cell activation is unclear. In earlier studies, we demonstrated that immunoglobulin free light chains (FLC) can trigger mast cells in an antigen-specific manner. Increased expression of FLC was observed within stroma of various human cancers including those of breast, colon, lung, pancreas, kidney and skin, and FLC expression co-localized with areas of mast cell infiltration. In a large cohort of breast cancer patients, FLC expression was shown associated with basal-like cancers with an aggressive phenotype. Moreover, lambda FLC was found expressed in areas of inflammatory infiltration and its expression was significantly associated with poor clinical outcome. Functional importance of FLCs was shown in a murine B16F10 melanoma model, where inhibition of FLC-mediated mast cell activation strongly reduced tumor growth. Collectively, this study identifies FLCs as a ligand in the pro-tumorigenic activation of mast cells. Blocking this pathway may open new avenues for the inhibition of tumor growth, while immunohistochemical staining of FLC may be helpful in the diagnosis and prognosis of cancer.
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Affiliation(s)
- Tom Groot Kormelink
- Division of Pharmacology, Utrecht Institute for Pharmaceutical Sciences, Faculty of Science, Utrecht University, Utrecht, The Netherlands
| | | | | | | | | | | | | | | | | | | | | | | | | | | | - Raymond M Schiffelers
- Laboratory of Clinical Chemistry and Hematology, University Medical Center Utrecht, Utrecht, The Netherlands
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Maciel TT, Moura IC, Hermine O. The role of mast cells in cancers. F1000PRIME REPORTS 2015; 7:09. [PMID: 25705392 PMCID: PMC4311277 DOI: 10.12703/p7-09] [Citation(s) in RCA: 78] [Impact Index Per Article: 7.8] [Reference Citation Analysis] [Abstract] [Download PDF] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
Mast cells are immune cells that accumulate in the tumors and their microenvironment during disease progression. Mast cells are armed with a wide array of receptors that sense environment modifications and, upon stimulation, they are able to secrete several biologically active factors involved in the modulation of tumor growth. For example, mast cells are able to secrete pro-angiogenic and growth factors but also pro- and anti-inflammatory mediators. Recent studies have allowed substantial progress in understanding the role of mast cells in tumorigenesis/disease progression but further studies are necessary to completely elucidate their impact in the pathophysiology of cancer. Here we review observations suggesting that mast cells could modulate tumor growth in humans. We also discuss the drawbacks related to observations from mast cell-deficient mouse models, which could have consequences in the determination of a potential causative relationship between mast cells and cancer. We believe that the understanding of the precise role of mast cells in tumor development and progression will be of critical importance for the development of new targeted therapies in human cancers.
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Affiliation(s)
- Thiago T. Maciel
- INSERM UMR 1163, Laboratory of cellular and molecular mechanisms of hematological disorders and therapeutic implications24 Boulevard du Montparnasse, 75015, ParisFrance
- Paris Descartes – Sorbonne Paris Cité University, Imagine Institute24 Boulevard du Montparnasse, 75015, ParisFrance
- CNRS ERL 825424 Boulevard du Montparnasse, 75015, ParisFrance
- Laboratory of Excellence GR-Ex24 Boulevard du Montparnasse, 75015, ParisFrance
- Centre de Référence National des Mastocytoses (CEREMAST)149 rue de Sèvres, 75015, ParisFrance
| | - Ivan C. Moura
- INSERM UMR 1163, Laboratory of cellular and molecular mechanisms of hematological disorders and therapeutic implications24 Boulevard du Montparnasse, 75015, ParisFrance
- Paris Descartes – Sorbonne Paris Cité University, Imagine Institute24 Boulevard du Montparnasse, 75015, ParisFrance
- CNRS ERL 825424 Boulevard du Montparnasse, 75015, ParisFrance
- Laboratory of Excellence GR-Ex24 Boulevard du Montparnasse, 75015, ParisFrance
- Centre de Référence National des Mastocytoses (CEREMAST)149 rue de Sèvres, 75015, ParisFrance
| | - Olivier Hermine
- INSERM UMR 1163, Laboratory of cellular and molecular mechanisms of hematological disorders and therapeutic implications24 Boulevard du Montparnasse, 75015, ParisFrance
- Paris Descartes – Sorbonne Paris Cité University, Imagine Institute24 Boulevard du Montparnasse, 75015, ParisFrance
- CNRS ERL 825424 Boulevard du Montparnasse, 75015, ParisFrance
- Laboratory of Excellence GR-Ex24 Boulevard du Montparnasse, 75015, ParisFrance
- Centre de Référence National des Mastocytoses (CEREMAST)149 rue de Sèvres, 75015, ParisFrance
- Service d'Hématologie clinique, Assistance Publique-Hôpitaux de Paris, Hôpital Necker149 rue de Sèvres, 75015, ParisFrance
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Inman KS, Francis AA, Murray NR. Complex role for the immune system in initiation and progression of pancreatic cancer. World J Gastroenterol 2014; 20:11160-11181. [PMID: 25170202 PMCID: PMC4145756 DOI: 10.3748/wjg.v20.i32.11160] [Citation(s) in RCA: 107] [Impact Index Per Article: 9.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/29/2013] [Revised: 01/27/2014] [Accepted: 04/16/2014] [Indexed: 02/06/2023] Open
Abstract
The immune system plays a complex role in the development and progression of pancreatic cancer. Inflammation can promote the formation of premalignant lesions and accelerate pancreatic cancer development. Conversely, pancreatic cancer is characterized by an immunosuppressive environment, which is thought to promote tumor progression and invasion. Here we review the current literature describing the role of the immune response in the progressive development of pancreatic cancer, with a focus on the mechanisms that drive recruitment and activation of immune cells at the tumor site, and our current understanding of the function of the immune cell types at the tumor. Recent clinical and preclinical data are reviewed, detailing the involvement of the immune response in pancreatitis and pancreatic cancer, including the role of specific cytokines and implications for disease outcome. Acute pancreatitis is characterized by a predominantly innate immune response, while chronic pancreatitis elicits an immune response that involves both innate and adaptive immune cells, and often results in profound systemic immune-suppression. Pancreatic adenocarcinoma is characterized by marked immune dysfunction driven by immunosuppressive cell types, tumor-promoting immune cells, and defective or absent inflammatory cells. Recent studies reveal that immune cells interact with cancer stem cells and tumor stromal cells, and these interactions have an impact on development and progression of pancreatic ductal adenocarcinoma (PDAC). Finally, current PDAC therapies are reviewed and the potential for harnessing the actions of the immune response to assist in targeting pancreatic cancer using immunotherapy is discussed.
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35
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LeMercier I, Chen W, Lines JL, Day M, Li J, Sergent P, Noelle RJ, Wang L. VISTA Regulates the Development of Protective Antitumor Immunity. Cancer Res 2014; 74:1933-44. [PMID: 24691994 PMCID: PMC4116689 DOI: 10.1158/0008-5472.can-13-1506] [Citation(s) in RCA: 372] [Impact Index Per Article: 33.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/18/2022]
Abstract
V-domain Ig suppressor of T-cell activation (VISTA) is a novel negative checkpoint ligand that is homologous to PD-L1 and suppresses T-cell activation. This study demonstrates the multiple mechanisms whereby VISTA relieves negative regulation by hematopoietic cells and enhances protective antitumor immunity. VISTA is highly expressed on myeloid cells and Foxp3(+)CD4(+) regulatory cells, but not on tumor cells within the tumor microenvironment (TME). VISTA monoclonal antibody (mAb) treatment increased the number of tumor-specific T cells in the periphery and enhanced the infiltration, proliferation, and effector function of tumor-reactive T cells within the TME. VISTA blockade altered the suppressive feature of the TME by decreasing the presence of monocytic myeloid-derived suppressor cells and increasing the presence of activated dendritic cells within the tumor microenvironment. In addition, VISTA blockade impaired the suppressive function and reduced the emergence of tumor-specific Foxp3(+)CD4(+) regulatory T cells. Consequently, VISTA mAb administration as a monotherapy significantly suppressed the growth of both transplantable and inducible melanoma. Initial studies explored a combinatorial regimen using VISTA blockade and a peptide-based cancer vaccine with TLR agonists as adjuvants. VISTA blockade synergized with the vaccine to effectively impair the growth of established tumors. Our study therefore establishes a foundation for designing VISTA-targeted approaches either as a monotherapy or in combination with additional immune-targeted strategies for cancer immunotherapy.
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Affiliation(s)
- Isabelle LeMercier
- Department of Microbiology and Immunology, The Geisel School of Medicine at Dartmouth, The Norris Cotton Cancer Center, 1 Medical Center Drive, Lebanon, NH 03756, USA
| | - Wenna Chen
- Department of Microbiology and Immunology, The Geisel School of Medicine at Dartmouth, The Norris Cotton Cancer Center, 1 Medical Center Drive, Lebanon, NH 03756, USA
| | - Janet L. Lines
- Medical Research Council Centre of Transplantation, Guy’s Hospital, King’s College London, King’s Health Partners, London, United Kingdom. Department of Immune Regulation and Intervention, King’s College, London, SE1 9RT
| | - Maria Day
- ImmuNext Inc., 16 Cavendish Court, Lebanon, NH 03766
| | - Jiannan Li
- Department of Microbiology and Immunology, The Geisel School of Medicine at Dartmouth, The Norris Cotton Cancer Center, 1 Medical Center Drive, Lebanon, NH 03756, USA
| | - Petra Sergent
- Department of Microbiology and Immunology, The Geisel School of Medicine at Dartmouth, The Norris Cotton Cancer Center, 1 Medical Center Drive, Lebanon, NH 03756, USA
| | - Randolph J. Noelle
- Department of Microbiology and Immunology, The Geisel School of Medicine at Dartmouth, The Norris Cotton Cancer Center, 1 Medical Center Drive, Lebanon, NH 03756, USA
- Medical Research Council Centre of Transplantation, Guy’s Hospital, King’s College London, King’s Health Partners, London, United Kingdom. Department of Immune Regulation and Intervention, King’s College, London, SE1 9RT
| | - Li Wang
- Department of Microbiology and Immunology, The Geisel School of Medicine at Dartmouth, The Norris Cotton Cancer Center, 1 Medical Center Drive, Lebanon, NH 03756, USA
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Oldford SA, Marshall JS. Mast cells as targets for immunotherapy of solid tumors. Mol Immunol 2014; 63:113-24. [PMID: 24698842 DOI: 10.1016/j.molimm.2014.02.020] [Citation(s) in RCA: 128] [Impact Index Per Article: 11.6] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/12/2013] [Revised: 02/26/2014] [Accepted: 02/27/2014] [Indexed: 01/09/2023]
Abstract
Mast cells have historically been studied mainly in the context of allergic disease. In recent years, we have come to understand the critical importance of mast cells in tissue remodeling events and their role as sentinel cells in the induction and development of effective immune responses to infection. Studies of the role of mast cells in tumor immunity are more limited. The pro-tumorigenic role of mast cells has been widely reported. However, mast cell infiltration predicts improved prognosis in some cancers, suggesting that their prognostic value may be dependent on other variables. Such factors may include the nature of local mast cell subsets and the various activation stimuli present within the tumor microenvironment. Experimental models have highlighted the importance of mast cells in orchestrating the anti-tumor events that follow immunotherapies that target innate immunity. Mast cells are long-lived tissue resident cells that are abundant around many solid tumors and are radiation resistant making them unique candidates for combined treatment modalities. This review will examine some of the key roles of mast cells in tumor immunity, with a focus on potential immunotherapeutic interventions that harness the sentinel role of mast cells.
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Affiliation(s)
- Sharon A Oldford
- Dalhousie Inflammation Group, Dalhousie University, Halifax, NS, Canada; Department of Microbiology and Immunology, Dalhousie University, Halifax, NS, Canada
| | - Jean S Marshall
- Dalhousie Inflammation Group, Dalhousie University, Halifax, NS, Canada; Department of Microbiology and Immunology, Dalhousie University, Halifax, NS, Canada.
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Pappa CA, Tsirakis G, Devetzoglou M, Zafeiri M, Vyzoukaki R, Androvitsanea A, Xekalou A, Sfiridaki K, Alexandrakis MG. Bone marrow mast cell density correlates with serum levels of VEGF and CXC chemokines ENA-78 and GRO-α in multiple myeloma. Tumour Biol 2014; 35:5647-51. [PMID: 24563338 DOI: 10.1007/s13277-014-1747-x] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/26/2013] [Accepted: 02/13/2014] [Indexed: 02/07/2023] Open
Abstract
Angiogenesis is a crucial process in growth and progression of multiple myeloma (MM). Mast cells (MCs) play an important role in MM angiogenesis. Various angiogenic mediators secreted by MCs regulate endothelial cell proliferation and function. Among them, ELR(+) CXC chemokines, such as growth-related oncogen-alpha (GRO-α) and epithelial neutrophil activating protein-78 (ENA-78), have been described as potential mediators in regulation of angiogenesis. The purpose of the study was to quantify MCs in bone marrow (BM) biopsies of MM patients, expressed as MC density (MCD), and correlate it with serum concentrations of vascular endothelial factor (VEGF), GRO-α, ENA-78. Fifty-four newly diagnosed MM patients and 22 healthy controls were studied. Tryptase was used for the immunohistochemical stain of MCs. VEGF, GRO-α, and ENA-78 were measured in sera by ELISA. MCD and serum levels of GRO-α, ENA-78, and VEGF were significantly higher in MM patients compared to controls (p<0.001 in all cases). MCD was significantly increasing with increased stage of the disease (p<0.001). Furthermore, significant correlations were found between MCD with VEGF, GRO-α, and ENA-78. These findings support that MCs participate in the pathophysiology of MM and is implicated in the angiogenic process and disease progression.
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Affiliation(s)
- C A Pappa
- Hematology Department, Venizelion General Hospital of Heraklion, Heraklion, Greece
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