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Fischer OW, Justesen TF, Gögenur DS, Madsen MT, Mortensen MB, Gögenur I, Orhan A. Long-Term Oncological Outcomes of Granulocyte Colony-Stimulating Factor (G-CSF) Treatment in Gastrointestinal Cancers: A Systematic Review and Meta-Analysis. Cancers (Basel) 2025; 17:1313. [PMID: 40282489 PMCID: PMC12026166 DOI: 10.3390/cancers17081313] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/24/2025] [Revised: 04/09/2025] [Accepted: 04/10/2025] [Indexed: 04/29/2025] Open
Abstract
BACKGROUND Granulocyte-colony stimulating factor (G-CSF) prophylaxis is widely used in gastrointestinal (GI) cancers. The use of G-CSF in GI cancers has not previously been investigated systematically in a meta-analysis. Thus, we systematically reviewed the literature to describe the G-CSF use and potential influence on long-term oncological outcomes in GI cancers. METHOD The literature search of this systematic review and meta-analysis was conducted in PubMed, Embase, Cochrane Library and Web of Science. The PRISMA-P guidelines were followed. Studies that reported data on patients with GI cancers undergoing oncological treatment with G-CSF prophylaxis were included. Outcomes of interest were overall survival (OS), progression-free survival (PFS) and adverse events (AE), specifically neutropenia grade III/IV. A time-to-event random-effects meta-analysis was conducted. Risk of bias was assessed using the Newcastle-Ottawa Scale and the Cochrane Risk of Bias Tool for Randomized Controlled Trials (RoB) tool. FINDINGS In total, 2452 articles were screened for eligibility. Ultimately, 13 studies were included with a total patient number of 2673. The included studies indicated a positive association between OS and G-CSF prophylaxis (HR 0.72, 95% CI: 0.56-0.91, I2: 54%, low quality evidence). No significant relation between G-CSF use and PFS was found in the pooled analyses (HR 0.74, 95% CI: 0.51-1.08, I2: 73%, moderate quality evidence). However, a positive effect of G-CSF use was found in the retrospective cohorts reporting data on PFS (HR 0.50, 95% CI: 0.32-0.77, I2: 0%). A marked drop in neutropenia grade III/IV rates was observed in patients treated with G-CSF (risk ratio (RR) 0.46, 95% CI: 0.28-0.77, I2: 72%, high quality evidence). INTERPRETATION G-CSF prophylaxis provides a reduction in neutropenia grade III/IV in patients with GI cancers (high level of certainty) and a favorable OS (low certainty), while PFS is unaffected (moderate certainty). Studies on PFS and G-CSF use are nonetheless limited.
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Affiliation(s)
- Oliver Wedel Fischer
- Center for Surgical Science, Department of Surgery, Zealand University Hospital, 4600 Køge, Denmark (A.O.)
| | - Tobias Freyberg Justesen
- Center for Surgical Science, Department of Surgery, Zealand University Hospital, 4600 Køge, Denmark (A.O.)
| | - Dilara Seyma Gögenur
- Center for Surgical Science, Department of Surgery, Zealand University Hospital, 4600 Køge, Denmark (A.O.)
| | - Michael Tvilling Madsen
- Center for Surgical Science, Department of Surgery, Zealand University Hospital, 4600 Køge, Denmark (A.O.)
- Department of Surgery, Slagelse Sygehus, 4200 Slagelse, Denmark
| | - Michael Bau Mortensen
- Odense PIPAC Center, Odense University Hospital, 5000 Odense, Denmark
- Odense Pancreas Center (OPAC), Odense University Hospital, 5000 Odense, Denmark
- Department of Clinical Research, Faculty of Health Sciences, University of Southern Denmark, 5000 Odense, Denmark
- Department of Surgery, Odense University Hospital, 5000 Odense, Denmark
| | - Ismail Gögenur
- Center for Surgical Science, Department of Surgery, Zealand University Hospital, 4600 Køge, Denmark (A.O.)
- Department of Clinical Medicine, University of Copenhagen, 2200 Copenhagen, Denmark
| | - Adile Orhan
- Center for Surgical Science, Department of Surgery, Zealand University Hospital, 4600 Køge, Denmark (A.O.)
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Ward AC. Secondary Neutropenias. Biomedicines 2025; 13:497. [PMID: 40002910 PMCID: PMC11853056 DOI: 10.3390/biomedicines13020497] [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: 01/21/2025] [Revised: 02/07/2025] [Accepted: 02/15/2025] [Indexed: 02/27/2025] Open
Abstract
Neutrophils are a critical component of immunity, particularly against bacteria and other pathogens, but also in inflammation and tissue repair. As a consequence, individuals with neutropenia, defined by a reduction in absolute neutrophil counts, exhibit a strong propensity to severe infections that typically present with muted symptoms. Neutropenias encompass a heterogeneous set of disorders, comprising primary neutropenias, in which specific genes are mutated, and the more common secondary neutropenias, which have diverse non-genetic causes. These include hematological and other cancers, involving both direct effects of the cancer itself and indirect impacts via the chemotherapeutic, biological agents and cell-based approaches used for treatment. Other significant causes of secondary neutropenias are non-chemotherapeutic drugs, autoimmune and other immune diseases, infections and nutrient deficiencies. These collectively act by impacting neutrophil production in the bone marrow and/or destruction throughout the body. This review describes the biological and clinical manifestations of secondary neutropenias, detailing their underlying causes and management, with a discussion of alternative and emerging therapeutic approaches.
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Affiliation(s)
- Alister C. Ward
- School of Medicine, Deakin University, Waurn Ponds, VIC 3216, Australia;
- Institute for Mental and Physical Health and Clinical Translation (IMPACT), Deakin University, Waurn Ponds, VIC 3216, Australia
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Tai YS, Leung JH, Wang SY, Leung HWC, Chan ALF. Association of Granulocyte Colony-Stimulating Factor Treatment with Risk of Brain Metastasis in Advanced Stage Breast Cancer. Int J Mol Sci 2024; 25:10756. [PMID: 39409083 PMCID: PMC11477282 DOI: 10.3390/ijms251910756] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/31/2024] [Revised: 10/02/2024] [Accepted: 10/03/2024] [Indexed: 10/20/2024] Open
Abstract
The routine use of granulocyte colony-stimulating factor (GCSF) is not recommended for the prevention or treatment of chemotherapy-induced neutropenia or febrile neutropenia because risks associated with certain types of cancers, distant organ metastases, and primary tumor growth cannot be excluded. We examined the association between GCSF use and the incidence of brain metastasis (BM), as well as BM-free survival (BMFS). This retrospective cohort study included 121 stage IV breast cancer patients without confirmed BM at the time of diagnosis and who received at least one course of systematic chemotherapy or target therapy at a tertiary teaching hospital between 1 January 2014 and 31 December 2022. The effect of GCSF use on BM was assessed with other confounding factors in Cox regression analyses. In this retrospective cohort, patients who received GCSF treatment had a significantly higher incidence of BM than those who did not (34.9% vs. 13.8%, p = 0.011). Univariate Cox regression analysis showed that GCSF use, menopause status, hormone treatment, HER2 treatment, cumulative dosage, dosage density, and neutropenia were independent risk factors for BMFS (p < 0.05). GCSF users had a higher risk of BM (adjusted HR: 2.538; 95% CI: 1.127-5.716, p = 0.025) than nonusers. BM risk was significantly associated with those with neutropenia (RR: 1.84, 95% CI: 1.21, 2.80) but not with those without neutropenia (RR: 0.59, 95% CI: 0.41-0.84, Interaction p-value < 0.05). The higher the dose density of GCSF, the higher the risk compared with those who do not use GCSF (p for trend < 0.01). These preliminary results suggest that GCSF is associated with BM in patients with stage IV breast cancer who did not have BM at initial diagnosis. Further comprehensively designed large-scale observational studies are needed to confirm our preliminary results.
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Affiliation(s)
- Yun-Sheng Tai
- Department of Breast Surgery, An-Nan Hospital, China Medical University, Tainan 709, Taiwan;
| | - John Hang Leung
- Department of Obstetrics and Gynecology, Ditmanson Medical Foundation Chia-Yi Christian Hospital, Chia-Yi 600, Taiwan;
| | - Shyh-Yau Wang
- Department of Radiology, An-Nan Hospital, China Medical University, Tainan 709, Taiwan;
| | - Henry W. C. Leung
- Department of Radiation Oncology, An-Nan Hospital, China Medical University, Tainan 709, Taiwan
| | - Agnes L. F. Chan
- Department of Pharmacy, Kaohsiung Show Chwan Memorial Hospital, Kaohsiung 821, Taiwan
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Tsukazaki Y, Ogino H, Okano Y, Kakiuchi S, Harada S, Toyoda Y, Matsumura Y, Ichihara S, Imakura T, Matsumoto R, Ozaki R, Ogawa E, Morita Y, Mitsuhashi A, Yabuki Y, Yoneda H, Hanibuchi M, Hase K, Takeuchi E, Haku T, Nishioka Y. Granulocyte colony-stimulating factor has the potential to attenuate the therapeutic efficacy of chemo-immunotherapy for extensive-stage small-cell lung cancer. Int J Clin Oncol 2024; 29:1451-1460. [PMID: 39009900 DOI: 10.1007/s10147-024-02586-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/06/2024] [Accepted: 07/10/2024] [Indexed: 07/17/2024]
Abstract
BACKGROUND Granulocyte colony-stimulating factor (G-CSF) has the potential to attenuate the anti-tumor immune responses of T-cells by increasing immune suppressive neutrophils and myeloid-derived suppressor cells. However, the clinical impact of G-CSF on the efficacy of immunotherapy remains unknown. This multi-center retrospective analysis evaluated the impact of G-CSF in patients with extensive-stage small-cell lung cancer (ES-SCLC) treated with chemo-immunotherapy. METHODS We analyzed 65 patients with ES-SCLC who completed four cycles of induction chemo-immunotherapy and evaluated the effects of G-CSF on progression-free survival (PFS), overall survival (OS), and a durable response to immunotherapy (defined as PFS ≥ 12 months). RESULTS Fifty patients (76.9%) received ≥ 1 dose of G-CSF. The PFS of the patients with G-CSF was poorer than that of the patients without G-CSF (median PFS 8.3 vs. 4.9 months, p = 0.009). The OS of the patients with G-CSF tended to be shorter, but not statistically significant, than that of the patients without G-CSF (median OS 24.3 vs. 16.4 months, p = 0.137). In the multivariate analysis, G-CSF administration was associated with poorer PFS (hazard ratio 2.78, 95% CI 1.36-5.69, p = 0.005) and was identified as a determinant of a durable response (odds ratio 0.18, 95% CI 0.04-0.80, p = 0.024). These results were consistent with other definitions of G-CSF administration (administration of ≥ 1 dose of pegfilgrastim, or either ≥ 5 doses of filgrastim or ≥ 1 dose of pegfilgrastim). CONCLUSIONS G-CSF has the potential to attenuate the efficacy of immunotherapy; therefore, the indication for G-CSF during chemo-immunotherapy should be carefully considered for ES-SCLC.
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Affiliation(s)
- Yuki Tsukazaki
- Department of Respiratory Medicine and Rheumatology, Graduate School of Biomedical Sciences, Tokushima University, 3-18-15, Kuramoto-Cho, Tokushima, 770-8503, Japan
| | - Hirokazu Ogino
- Department of Respiratory Medicine and Rheumatology, Graduate School of Biomedical Sciences, Tokushima University, 3-18-15, Kuramoto-Cho, Tokushima, 770-8503, Japan.
| | - Yoshio Okano
- Department of Respiratory Medicine, National Hospital Organization Kochi Hospital, 1-2-25 Asakuranishimachi, Kochi, 780-8507, Japan
| | - Soji Kakiuchi
- Department of Respiratory Medicine, Tokushima Prefectural Central Hospital, 1-10-3, Kuramoto-Cho, Tokushima, 770-8539, Japan
| | - Shoko Harada
- Department of Respiratory Medicine, Tokushima Municipal Hospital, 2-34 Kitajosanjima-Cho, Tokushima, 770-0812, Japan
| | - Yuko Toyoda
- Department of Internal Medicine, Japanese Red Cross Kochi Hospital, 1-4-63-11, Hadaminamimachi, Kochi, 780-8562, Japan
| | - Yugo Matsumura
- Department of Respiratory Medicine, National Hospital Organization Kochi Hospital, 1-2-25 Asakuranishimachi, Kochi, 780-8507, Japan
| | - Seiya Ichihara
- Department of Respiratory Medicine, National Hospital Organization Kochi Hospital, 1-2-25 Asakuranishimachi, Kochi, 780-8507, Japan
| | - Takeshi Imakura
- Department of Respiratory Medicine, Tokushima Prefectural Central Hospital, 1-10-3, Kuramoto-Cho, Tokushima, 770-8539, Japan
| | - Rikako Matsumoto
- Department of Respiratory Medicine and Rheumatology, Graduate School of Biomedical Sciences, Tokushima University, 3-18-15, Kuramoto-Cho, Tokushima, 770-8503, Japan
| | - Ryohiko Ozaki
- Department of Respiratory Medicine and Rheumatology, Graduate School of Biomedical Sciences, Tokushima University, 3-18-15, Kuramoto-Cho, Tokushima, 770-8503, Japan
| | - Ei Ogawa
- Department of Respiratory Medicine and Rheumatology, Graduate School of Biomedical Sciences, Tokushima University, 3-18-15, Kuramoto-Cho, Tokushima, 770-8503, Japan
| | - Yutaka Morita
- Department of Respiratory Medicine and Rheumatology, Graduate School of Biomedical Sciences, Tokushima University, 3-18-15, Kuramoto-Cho, Tokushima, 770-8503, Japan
- Department of Internal Medicine, Japanese Red Cross Kochi Hospital, 1-4-63-11, Hadaminamimachi, Kochi, 780-8562, Japan
| | - Atsushi Mitsuhashi
- Department of Respiratory Medicine and Rheumatology, Graduate School of Biomedical Sciences, Tokushima University, 3-18-15, Kuramoto-Cho, Tokushima, 770-8503, Japan
| | - Yohei Yabuki
- Department of Respiratory Medicine and Rheumatology, Graduate School of Biomedical Sciences, Tokushima University, 3-18-15, Kuramoto-Cho, Tokushima, 770-8503, Japan
| | - Hiroto Yoneda
- Department of Respiratory Medicine and Rheumatology, Graduate School of Biomedical Sciences, Tokushima University, 3-18-15, Kuramoto-Cho, Tokushima, 770-8503, Japan
| | - Masaki Hanibuchi
- Department of Respiratory Medicine and Rheumatology, Graduate School of Biomedical Sciences, Tokushima University, 3-18-15, Kuramoto-Cho, Tokushima, 770-8503, Japan
- Department of Community Medicine for Respirology, Hematology and Metabolism, Graduate School of Biomedical Sciences, Tokushima University, 3-18-15, Kuramoto-Cho, Tokushima, 770-8503, Japan
| | - Kayoko Hase
- Department of Respiratory Medicine, Tokushima Municipal Hospital, 2-34 Kitajosanjima-Cho, Tokushima, 770-0812, Japan
| | - Eiji Takeuchi
- Department of Respiratory Medicine, National Hospital Organization Kochi Hospital, 1-2-25 Asakuranishimachi, Kochi, 780-8507, Japan
- Department of Clinical Investigation, National Hospital Organization Kochi Hospital, 1-2-25 Asakuranishimachi, Kochi, 780-8507, Japan
| | - Takashi Haku
- Department of Respiratory Medicine, Tokushima Prefectural Central Hospital, 1-10-3, Kuramoto-Cho, Tokushima, 770-8539, Japan
| | - Yasuhiko Nishioka
- Department of Respiratory Medicine and Rheumatology, Graduate School of Biomedical Sciences, Tokushima University, 3-18-15, Kuramoto-Cho, Tokushima, 770-8503, Japan
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Yang Z, Zeng H, Li J, Zeng N, Zhang Q, Hou K, Li J, Yu J, Wu Y. Dissecting the emerging role of cancer-associated adipocyte-derived cytokines in remodeling breast cancer progression. Heliyon 2024; 10:e35200. [PMID: 39161825 PMCID: PMC11332884 DOI: 10.1016/j.heliyon.2024.e35200] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/10/2024] [Revised: 07/04/2024] [Accepted: 07/24/2024] [Indexed: 08/21/2024] Open
Abstract
Breast cancer has been reported to transcend lung cancer as the most commonly diagnosed cancer in women all over the world. Adipocytes, serving as energy storage and endocrine cells, are the major stromal cells in the breast. Cancer-associated adipocytes (CAAs) are adjacent and dedifferentiated adipocytes located at the invasive front of human breast tumors. Adipocytes can transform into CAA phenotype with morphological and biological changes under the remodeling of breast cancer cells. CAAs play an essential role in breast cancer progression, including remodeling the tumor microenvironment (TME), regulating immunity, and interacting with breast cancer cells. CAAs possess peculiar secretomes and are accordingly capable to promote proliferation, invasiveness, angiogenesis, metastasis, immune escape, and drug resistance of breast cancer cells. There is a complex and coordinated crosstalk among CAAs, immune cells, and breast cancer cells. CAAs can release a variety of cytokines, including IL-6, IL-8, IL-1β, CCL5, CCL2, VEGF, G-CSF, IGF-1, and IGFBP, thereby promoting immune cell recruitment and macrophage polarization, and ultimately stimulating malignant behaviors in breast cancer cells. Here, we aim to provide a comprehensive description of CAA-derived cytokines, including their impact on cancer cell behaviors, immune regulation, breast cancer diagnosis, and treatment. A deeper understanding of CAA performance and interactions with specific TME cell populations will provide better strategies for cancer treatment and breast reconstruction after mastectomy.
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Affiliation(s)
- Zihui Yang
- Department of Plastic and Cosmetic Surgery, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China
| | - Hong Zeng
- Department of Plastic and Cosmetic Surgery, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China
| | - Jia Li
- Department of Plastic and Cosmetic Surgery, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China
| | - Ning Zeng
- Department of Plastic and Cosmetic Surgery, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China
| | - Qi Zhang
- Department of Plastic and Cosmetic Surgery, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China
- Xianning Medical College, Hubei University of Science and Technology, Xianning, 437000, Hubei, China
| | - Kai Hou
- Department of Plastic and Cosmetic Surgery, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China
| | - Jie Li
- Department of Thyroid and Breast Surgery, Shenzhen Qianhai Shekou Free Trade Zone Hospital, Shenzhen, 518067, China
| | - Jing Yu
- Department of Plastic and Cosmetic Surgery, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China
| | - Yiping Wu
- Department of Plastic and Cosmetic Surgery, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China
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Deo A, Sleeman JP, Shaked Y. The role of host response to chemotherapy: resistance, metastasis and clinical implications. Clin Exp Metastasis 2024; 41:495-507. [PMID: 37999904 DOI: 10.1007/s10585-023-10243-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/28/2023] [Accepted: 11/06/2023] [Indexed: 11/25/2023]
Abstract
Chemotherapy remains the primary treatment for most metastatic cancers. However, the response to chemotherapy and targeted agents is often transient, and concurrent development of resistance is the primary impediment to effective cancer therapy. Strategies to overcome resistance to treatment have focused on cancer cell intrinsic factors and the tumor microenvironment (TME). Recent evidence indicates that systemic chemotherapy has a significant impact on the host that either facilitates tumor growth, allowing metastatic spread, or renders treatment ineffective. These host responses include the release of bone marrow-derived cells, activation of stromal cells in the TME, and induction of different molecular effectors. Here, we provide an overview of chemotherapy-induced systemic host responses that support tumor aggressiveness and metastasis, and which contribute to therapy resistance. Studying host responses to chemotherapy provides a solid basis for the development of adjuvant strategies to improve treatment outcomes and delay resistance to chemotherapy. This review discusses the emerging field of host response to cancer therapy, and its preclinical and potential clinical implications, explaining how under certain circumstances, these host effects contribute to metastasis and resistance to chemotherapy.
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Affiliation(s)
- Abhilash Deo
- Department of Cell Biology and Cancer Science, Rappaport Technion Integrated Cancer Center, Technion - Israel Institute of Technology, Haifa, Israel
| | - Jonathan P Sleeman
- European Centre for Angioscience (ECAS), Medical Faculty Mannheim, University of Heidelberg, Mannheim, Germany
- Karlsruhe Institute for Technology (KIT), IBCS-BIP, Campus Nord, 76344, Eggenstein- Leopoldshafen, Germany
| | - Yuval Shaked
- Department of Cell Biology and Cancer Science, Rappaport Technion Integrated Cancer Center, Technion - Israel Institute of Technology, Haifa, Israel.
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Xu MY, Zeng N, Liu CQ, Sun JX, An Y, Zhang SH, Xu JZ, Zhong XY, Ma SY, He HD, Hu J, Xia QD, Wang SG. Enhanced cellular therapy: revolutionizing adoptive cellular therapy. Exp Hematol Oncol 2024; 13:47. [PMID: 38664743 PMCID: PMC11046957 DOI: 10.1186/s40164-024-00506-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/13/2023] [Accepted: 03/31/2024] [Indexed: 04/28/2024] Open
Abstract
Enhanced cellular therapy has emerged as a novel concept following the basis of cellular therapy. This treatment modality applied drugs or biotechnology to directly enhance or genetically modify cells to enhance the efficacy of adoptive cellular therapy (ACT). Drugs or biotechnology that enhance the killing ability of immune cells include immune checkpoint inhibitors (ICIs) / antibody drugs, small molecule inhibitors, immunomodulatory factors, proteolysis targeting chimera (PROTAC), oncolytic virus (OV), etc. Firstly, overcoming the inhibitory tumor microenvironment (TME) can enhance the efficacy of ACT, which can be achieved by blocking the immune checkpoint. Secondly, cytokines or cytokine receptors can be expressed by genetic engineering or added directly to adoptive cells to enhance the migration and infiltration of adoptive cells to tumor cells. Moreover, multi-antigen chimeric antigen receptors (CARs) can be designed to enhance the specific recognition of tumor cell-related antigens, and OVs can also stimulate antigen release. In addition to inserting suicide genes into adoptive cells, PROTAC technology can be used as a safety switch or degradation agent of immunosuppressive factors to enhance the safety and efficacy of adoptive cells. This article comprehensively summarizes the mechanism, current situation, and clinical application of enhanced cellular therapy, describing potential improvements to adoptive cellular therapy.
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Affiliation(s)
- Meng-Yao Xu
- Department and Institute of Urology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, No.1095 Jiefang Avenue, Wuhan, 430030, China
| | - Na Zeng
- Department and Institute of Urology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, No.1095 Jiefang Avenue, Wuhan, 430030, China
| | - Chen-Qian Liu
- Department and Institute of Urology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, No.1095 Jiefang Avenue, Wuhan, 430030, China
| | - Jian-Xuan Sun
- Department and Institute of Urology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, No.1095 Jiefang Avenue, Wuhan, 430030, China
| | - Ye An
- Department and Institute of Urology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, No.1095 Jiefang Avenue, Wuhan, 430030, China
| | - Si-Han Zhang
- Department and Institute of Urology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, No.1095 Jiefang Avenue, Wuhan, 430030, China
| | - Jin-Zhou Xu
- Department and Institute of Urology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, No.1095 Jiefang Avenue, Wuhan, 430030, China
| | - Xing-Yu Zhong
- Department and Institute of Urology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, No.1095 Jiefang Avenue, Wuhan, 430030, China
| | - Si-Yang Ma
- Department and Institute of Urology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, No.1095 Jiefang Avenue, Wuhan, 430030, China
| | - Hao-Dong He
- Department and Institute of Urology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, No.1095 Jiefang Avenue, Wuhan, 430030, China
| | - Jia Hu
- Department and Institute of Urology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, No.1095 Jiefang Avenue, Wuhan, 430030, China
| | - Qi-Dong Xia
- Department and Institute of Urology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, No.1095 Jiefang Avenue, Wuhan, 430030, China.
| | - Shao-Gang Wang
- Department and Institute of Urology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, No.1095 Jiefang Avenue, Wuhan, 430030, China.
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Luo S, Li P, Zhang A, Meng L, Huang L, Wu X, Cheng H, Tu H, Gong X. G-CSF improving combined whole brain radiotherapy and immunotherapy prognosis of non-small cell lung cancer brain metastases. Int Immunopharmacol 2024; 130:111705. [PMID: 38412673 DOI: 10.1016/j.intimp.2024.111705] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/05/2023] [Revised: 02/04/2024] [Accepted: 02/13/2024] [Indexed: 02/29/2024]
Abstract
OBJECTIVE To evaluate the therapeutic advantage of G-CSF to whole brain radiotherapy (WBRT) in combination with immunotherapy as a first-line treatment for non-small cell lung cancer (NSCLC) brain metastases (BMs). METHODS In this retrospective study, 117 patients (37 in G-CSF group and 80 in no G-CSF group) who underwent first-line WBRT combined with immunotherapy were enrolled. Their survival, intracranial response, BM-related symptoms and toxicity were evaluated. RESULTS The overall survival (OS) of patients in G-CSF group was significantly improved compared to patients no G-CSF group (median time: 14.8 vs 10.2 months; HR: 0.61, 95 % CI: 0.38-0.97, p = 0.035). However, there were no significant differences in intracranial responses between the two groups (p > 0.05). The G-CSF group exhibited a significantly higher rate of relief from BM-related symptoms compared to the no G-CSF group (91.7 % vs 59.5 %, p = 0.037). Cox proportional hazards regression analyses indicated that after-treatment ALC > 0.9 × 10^9/L (HR 0.57, 95 % CI 0.32-0.99, p = 0.046) and Hb > 110 g/dL (HR 0.41, 95 % CI 0.24-0.71, p = 0.001) were significant potential factors associated with extended OS. The addition of G-CSF was well tolerated and effectively reduced the incidence of neutropenia (0 % vs 5.0 %, p = 0.17). CONCLUSION Integrating G-CSF with WBRT and immunotherapy as a first-line treatment for NSCLC-BMs has exhibited significant efficacy and favorable tolerability.
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Affiliation(s)
- Shilan Luo
- Department of Radiation Oncology, Shanghai Pulmonary Hospital, Tongji University School of Medicine, Shanghai, China
| | - Peng Li
- Department of Radiation Oncology, Shanghai Pulmonary Hospital, Tongji University School of Medicine, Shanghai, China
| | - Anqi Zhang
- Department of Radiation Oncology, Shanghai Pulmonary Hospital, Tongji University School of Medicine, Shanghai, China
| | - Lu Meng
- Department of Radiation Oncology, Shanghai Pulmonary Hospital, Tongji University School of Medicine, Shanghai, China
| | - Litang Huang
- Department of Radiation Oncology, Shanghai Pulmonary Hospital, Tongji University School of Medicine, Shanghai, China
| | - Xiaoting Wu
- Department of Radiation Oncology, Shanghai Pulmonary Hospital, Tongji University School of Medicine, Shanghai, China
| | - Hongxia Cheng
- Department of Radiation Oncology, Shanghai Pulmonary Hospital, Tongji University School of Medicine, Shanghai, China
| | - Hongbin Tu
- Department of Integrated TCM & Western Medicine, Shanghai Pulmonary Hospital, Tongji University School of Medicine, Shanghai, China
| | - Xiaomei Gong
- Department of Radiation Oncology, Shanghai Pulmonary Hospital, Tongji University School of Medicine, Shanghai, China.
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Pettinella F, Mariotti B, Lattanzi C, Bruderek K, Donini M, Costa S, Marini O, Iannoto G, Gasperini S, Caveggion E, Castellucci M, Calzetti F, Bianchetto-Aguilera F, Gardiman E, Giani M, Dusi S, Cantini M, Vassanelli A, Pavone D, Milella M, Pilotto S, Biondani P, Höing B, Schleupner MC, Hussain T, Hadaschik B, Kaspar C, Visco C, Tecchio C, Koenderman L, Bazzoni F, Tamassia N, Brandau S, Cassatella MA, Scapini P. Surface CD52, CD84, and PTGER2 mark mature PMN-MDSCs from cancer patients and G-CSF-treated donors. Cell Rep Med 2024; 5:101380. [PMID: 38242120 PMCID: PMC10897522 DOI: 10.1016/j.xcrm.2023.101380] [Citation(s) in RCA: 7] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/07/2023] [Revised: 08/11/2023] [Accepted: 12/18/2023] [Indexed: 01/21/2024]
Abstract
Precise molecular characterization of circulating polymorphonuclear myeloid-derived suppressor cells (PMN-MDSCs) is hampered by their mixed composition of mature and immature cells and lack of specific markers. Here, we focus on mature CD66b+CD10+CD16+CD11b+ PMN-MDSCs (mPMN-MDSCs) from either cancer patients or healthy donors receiving G-CSF for stem cell mobilization (GDs). By RNA sequencing (RNA-seq) experiments, we report the identification of a distinct gene signature shared by the different mPMN-MDSC populations under investigation, also validated in mPMN-MDSCs from GDs and tumor-associated neutrophils (TANs) by single-cell RNA-seq (scRNA-seq) experiments. Analysis of such a gene signature uncovers a specific transcriptional program associated with mPMN-MDSC differentiation and allows us to identify that, in patients with either solid or hematologic tumors and in GDs, CD52, CD84, and prostaglandin E receptor 2 (PTGER2) represent potential mPMN-MDSC-associated markers. Altogether, our findings indicate that mature PMN-MDSCs distinctively undergo specific reprogramming during differentiation and lay the groundwork for selective immunomonitoring, and eventually targeting, of mature PMN-MDSCs.
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Affiliation(s)
- Francesca Pettinella
- Section of General Pathology, Department of Medicine, University of Verona, 37134 Verona, Italy
| | - Barbara Mariotti
- Section of General Pathology, Department of Medicine, University of Verona, 37134 Verona, Italy
| | - Chiara Lattanzi
- Section of General Pathology, Department of Medicine, University of Verona, 37134 Verona, Italy
| | - Kirsten Bruderek
- Research Division, Department of Otorhinolaryngology, University Hospital Essen, 45122 Essen, Germany
| | - Marta Donini
- Section of General Pathology, Department of Medicine, University of Verona, 37134 Verona, Italy
| | - Sara Costa
- Section of General Pathology, Department of Medicine, University of Verona, 37134 Verona, Italy
| | - Olivia Marini
- Section of General Pathology, Department of Medicine, University of Verona, 37134 Verona, Italy
| | - Giulia Iannoto
- Section of General Pathology, Department of Medicine, University of Verona, 37134 Verona, Italy
| | - Sara Gasperini
- Section of General Pathology, Department of Medicine, University of Verona, 37134 Verona, Italy
| | - Elena Caveggion
- Section of General Pathology, Department of Medicine, University of Verona, 37134 Verona, Italy
| | | | - Federica Calzetti
- Section of General Pathology, Department of Medicine, University of Verona, 37134 Verona, Italy
| | | | - Elisa Gardiman
- Section of General Pathology, Department of Medicine, University of Verona, 37134 Verona, Italy
| | - Matteo Giani
- Section of General Pathology, Department of Medicine, University of Verona, 37134 Verona, Italy
| | - Stefano Dusi
- Section of General Pathology, Department of Medicine, University of Verona, 37134 Verona, Italy
| | - Maurizio Cantini
- Transfusion Medicine Department, University and Hospital Trust (AOUI), Verona, Italy
| | - Aurora Vassanelli
- Transfusion Medicine Department, University and Hospital Trust (AOUI), Verona, Italy
| | - Denise Pavone
- Transfusion Medicine Department, University and Hospital Trust (AOUI), Verona, Italy
| | - Michele Milella
- Section of Innovation Biomedicine - Oncology Area, Department of Engineering for Innovation Medicine (DIMI), University of Verona, Verona, Italy
| | - Sara Pilotto
- Section of Innovation Biomedicine - Oncology Area, Department of Engineering for Innovation Medicine (DIMI), University of Verona, Verona, Italy
| | - Pamela Biondani
- Section of Oncology, University and Hospital Trust (AOUI) of Verona, Verona, Italy
| | - Benedikt Höing
- Department of Otorhinolaryngology, University Hospital Essen, Essen, Germany
| | | | - Timon Hussain
- Department of Otorhinolaryngology, University Hospital Essen, Essen, Germany
| | - Boris Hadaschik
- Department of Urology, University Hospital Essen, Essen, Germany
| | - Cordelia Kaspar
- Department of Urology, University Hospital Essen, Essen, Germany
| | - Carlo Visco
- Section of Hematology and Bone Marrow Transplant Unit, Department of Engineering for Innovation Medicine (DIMI), University of Verona, Verona, Italy
| | - Cristina Tecchio
- Section of Hematology and Bone Marrow Transplant Unit, Department of Engineering for Innovation Medicine (DIMI), University of Verona, Verona, Italy
| | - Leo Koenderman
- Department of Respiratory Medicine and Center for Translational Immunology, University Medical Center Utrecht, 3584CX Utrecht, the Netherlands
| | - Flavia Bazzoni
- Section of General Pathology, Department of Medicine, University of Verona, 37134 Verona, Italy
| | - Nicola Tamassia
- Section of General Pathology, Department of Medicine, University of Verona, 37134 Verona, Italy
| | - Sven Brandau
- Research Division, Department of Otorhinolaryngology, University Hospital Essen, 45122 Essen, Germany; German Cancer Consortium, Partner Site Essen-Düsseldorf, Essen, Germany
| | - Marco A Cassatella
- Section of General Pathology, Department of Medicine, University of Verona, 37134 Verona, Italy.
| | - Patrizia Scapini
- Section of General Pathology, Department of Medicine, University of Verona, 37134 Verona, Italy.
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Robinson MD, McNamara MG, Clouston HW, Sutton PA, Hubner RA, Valle JW. Patients Undergoing Systemic Anti-Cancer Therapy Who Require Surgical Intervention: What Surgeons Need to Know. Cancers (Basel) 2023; 15:3781. [PMID: 37568597 PMCID: PMC10417541 DOI: 10.3390/cancers15153781] [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: 06/13/2023] [Revised: 07/15/2023] [Accepted: 07/25/2023] [Indexed: 08/13/2023] Open
Abstract
As part of routine cancer care, patients may undergo elective surgery with the aim of long-term cure. Some of these patients will receive systemic anti-cancer therapy (SACT) in the neoadjuvant and adjuvant settings. The majority of patients, usually with locally advanced or metastatic disease, will receive SACT with palliative intent. These treatment options are expanding beyond traditional chemotherapy to include targeted therapies, immunotherapy, hormone therapy, radionuclide therapy and gene therapy. During treatment, some patients will require surgical intervention on an urgent or emergency basis. This narrative review examined the evidence base for SACT-associated surgical risk and the precautions that a surgical team should consider in patients undergoing SACT.
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Affiliation(s)
- Matthew D. Robinson
- Division of Cancer Sciences, School of Medical Sciences, Faculty of Biology Medicine and Health, The University of Manchester, Manchester M13 9NT, UK
| | - Mairéad G. McNamara
- Division of Cancer Sciences, School of Medical Sciences, Faculty of Biology Medicine and Health, The University of Manchester, Manchester M13 9NT, UK
- Department of Medical Oncology, ENETS Centre of Excellence, The Christie NHS Foundation Trust, Wilmslow Road, Manchester M20 4BX, UK
| | - Hamish W. Clouston
- Division of Cancer Sciences, School of Medical Sciences, Faculty of Biology Medicine and Health, The University of Manchester, Manchester M13 9NT, UK
- Colorectal and Peritoneal Oncology Centre, The Christie NHS Foundation Trust, Wilmslow Road, Manchester M20 4BX, UK
| | - Paul A. Sutton
- Division of Cancer Sciences, School of Medical Sciences, Faculty of Biology Medicine and Health, The University of Manchester, Manchester M13 9NT, UK
- Colorectal and Peritoneal Oncology Centre, The Christie NHS Foundation Trust, Wilmslow Road, Manchester M20 4BX, UK
| | - Richard A. Hubner
- Division of Cancer Sciences, School of Medical Sciences, Faculty of Biology Medicine and Health, The University of Manchester, Manchester M13 9NT, UK
- Department of Medical Oncology, ENETS Centre of Excellence, The Christie NHS Foundation Trust, Wilmslow Road, Manchester M20 4BX, UK
| | - Juan W. Valle
- Division of Cancer Sciences, School of Medical Sciences, Faculty of Biology Medicine and Health, The University of Manchester, Manchester M13 9NT, UK
- Department of Medical Oncology, ENETS Centre of Excellence, The Christie NHS Foundation Trust, Wilmslow Road, Manchester M20 4BX, UK
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11
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Li L, Hou M, Fang S. Application of colony-stimulating factor 3 in determining the prognosis of high-grade gliomas based on magnetic resonance imaging radiomics. Heliyon 2023; 9:e15325. [PMID: 37095939 PMCID: PMC10122032 DOI: 10.1016/j.heliyon.2023.e15325] [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: 11/10/2022] [Revised: 04/02/2023] [Accepted: 04/03/2023] [Indexed: 04/26/2023] Open
Abstract
Rationale and objectives Radiomics is a promising, non-invasive method for determining the prognosis of high-grade glioma (HGG). The connection between radiomics and the HGG prognostic biomarker is still insufficient. Materials and methods In this study, we collected the pathological, clinical, RNA-sequencing, and enhanced MRI data of HGG from TCIA and TCGA databases. We characterized the prognostic value of CSF3. Kaplan-Meier (KM) analysis, univariate and multivariate Cox regression, subgroup analysis, Spearman analysis, and gene set variation analysis enrichment were used to elucidate the prognostic value of the CSF3 gene and the correlation between CSF3 and tumor features. We used CIBERSORT to analyze the correlation between CSF3 and cancer immune infiltrates. Logistic regression (LR) and support vector machine methods (SVM) were used to build the radiomics models for the prognosis prediction of HGG based on the expression of CSF3. Results Based on the radiomics score calculated from LR model, 182 patients with HGG from TCGA database were divided into radiomics score (RS) high and low groups. CSF3 expression varied between tumor and normal group tissues. CSF3 expression was found to be a significant risk factor for survival outcomes. A positive association was found between CSF3 expression and immune infiltration. The radiomics model based on both LR and SVM methods showed high clinical practicability. Conclusion The results showed that CSF3 has a prognostic value in HGG. The developed radiomics models can predict the expression of CSF3, and further validate the predictions of the radiomics models for HGG.
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Affiliation(s)
- Leina Li
- Department of Anesthesiology, The Second Affiliated Hospital of Dalian Medical University, Dalian, Liaoning, China
- Laboratory Department of Cell Biology, College of Basic Medical Sciences, Dalian Medical University, Dalian, Liaoning, China
- Corresponding author. Department of Anesthesiology, The Second Affiliated Hospital of Dalian Medical University, Dalian, Liaoning, China.
| | - Meidan Hou
- Department of Radiology, The Second Affiliated Hospital of Dalian Medical University Dalian, Liaoning, China
| | - Shaobo Fang
- Department of Medical Imaging, Zhengzhou University People’s Hospital & Henan Provincial People’s Hospital, Zhengzhou, Henan, China
- Academy of Medical Sciences, Zhengzhou University, Zhengzhou, Henan, China
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12
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Fujita K, Okubo A, Nakamura T, Takeuchi N. Disseminated carcinomatosis of the bone marrow caused by granulocyte colony-stimulating factor: A case report and review of literature. World J Gastrointest Oncol 2022; 14:2077-2084. [PMID: 36310701 PMCID: PMC9611438 DOI: 10.4251/wjgo.v14.i10.2077] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/21/2022] [Revised: 07/08/2022] [Accepted: 08/21/2022] [Indexed: 02/05/2023] Open
Abstract
BACKGROUND Disseminated carcinomatosis of the bone marrow (DCBM) is a widespread metastasis with a hematologic disorder that is mainly caused by gastric cancer. Although it commonly occurs as a manifestation of recurrence long after curative treatment, the precise mechanism of relapse from dormant status remains unclear. Granulocyte colony-stimulating factor (G-CSF) can promote cancer progression and invasion in various cancers. However, the potential of G-CSF to trigger recurrence from a cured malignancy has not been reported.
CASE SUMMARY A 55-year-old Japanese woman was diagnosed with Ewing sarcoma localized on the fifth lumbar vertebrae 6 years after curative gastrectomy for T1 gastric cancer. After palliative surgery to release nerve compression, pathological diagnosis of the resected specimen was followed by curative radiation and chemotherapy. During treatment, G-CSF was administered 32 times for severe neutropenia prophylaxis. Eight months after completing definitive treatment, she complained of severe back pain and was diagnosed as multiple bone metastases with DCBM from gastric cancer. Despite palliative chemotherapy, she died of disseminated intravascular coagulation 13 d after the diagnosis. Immunohistochemical examination of the autopsied bone marrow confirmed a diffuse positive staining for the G-CSF receptor (G-CSFR) in the relapsed gastric cancer cell cytoplasm, whereas the primary lesion cancer cells showed negative staining for G-CSFR. In this case, G-CSF administration may have been the key trigger for the disseminated relapse of a dormant gastric cancer.
CONCLUSION When administering G-CSF to cancer survivors, recurrence of a preceding cancer should be monitored even after curative treatment.
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Affiliation(s)
- Kengo Fujita
- Department of Medical Oncology, Ina Central Hospital, Nagano 396-8555, Japan
| | - Ayaka Okubo
- Department of Medical Oncology, Ina Central Hospital, Nagano 396-8555, Japan
| | - Toshitsugu Nakamura
- Department of Diagnostic Pathology, Ina Central Hospital, Nagano 396-8555, Japan
| | - Nobumichi Takeuchi
- Department of Medical Oncology, Ina Central Hospital, Nagano 396-8555, Japan
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13
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High Neutrophil-to-Lymphocyte Ratio Facilitates Cancer Growth-Currently Marketed Drugs Tadalafil, Isotretinoin, Colchicine, and Omega-3 to Reduce It: The TICO Regimen. Cancers (Basel) 2022; 14:cancers14194965. [PMID: 36230888 PMCID: PMC9564173 DOI: 10.3390/cancers14194965] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/07/2022] [Revised: 10/03/2022] [Accepted: 10/03/2022] [Indexed: 11/22/2022] Open
Abstract
Simple Summary Several elements that are composed of, or related to, neutrophils, have been shown to inhibit strong immune responses to cancer and promote cancers’ growth. This paper presents the collected data showing these elements and how their coordinated actions as an ensemble facilitate growth in the common cancers. The paper goes on to present a drug regimen, TICO, designed to reduce the cancer growth enhancing effects of the neutrophil related elements. TICO uses four already marketed, readily available generic drugs, repurposed to inhibit neutrophil centered growth facilitation of cancer. Abstract This paper presents remarkably uniform data showing that higher NLR is a robust prognostic indicator of shorter overall survival across the common metastatic cancers. Myeloid derived suppressor cells, the NLRP3 inflammasome, neutrophil extracellular traps, and absolute neutrophil count tend to all be directly related to the NLR. They, individually and as an ensemble, contribute to cancer growth and metastasis. The multidrug regimen presented in this paper, TICO, was designed to decrease the NLR with potential to also reduce the other neutrophil related elements favoring malignant growth. TICO is comprised of already marketed generic drugs: the phosphodiesterase 5 inhibitor tadalafil, used to treat inadequate erections; isotretinoin, the retinoid used for acne treatment; colchicine, a standard gout (podagra) treatment; and the common fish oil supplement omega-3 polyunsaturated fatty acids. These individually impose low side effect burdens. The drugs of TICO are old, cheap, well known, and available worldwide. They all have evidence of lowering the NLR or the growth contributing elements related to the NLR when clinically used in general medicine as reviewed in this paper.
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14
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Zhao Y, Bai Y, Shen M, Li Y. Therapeutic strategies for gastric cancer targeting immune cells: Future directions. Front Immunol 2022; 13:992762. [PMID: 36225938 PMCID: PMC9549957 DOI: 10.3389/fimmu.2022.992762] [Citation(s) in RCA: 20] [Impact Index Per Article: 6.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/13/2022] [Accepted: 08/29/2022] [Indexed: 11/13/2022] Open
Abstract
Gastric cancer (GC) is a malignancy with a high incidence and mortality, and the emergence of immunotherapy has brought survival benefits to GC patients. Compared with traditional therapy, immunotherapy has the advantages of durable response, long-term survival benefits, and lower toxicity. Therefore, targeted immune cells are the most promising therapeutic strategy in the field of oncology. In this review, we introduce the role and significance of each immune cell in the tumor microenvironment of GC and summarize the current landscape of immunotherapy in GC, which includes immune checkpoint inhibitors, adoptive cell therapy (ACT), dendritic cell (DC) vaccines, reduction of M2 tumor-associated macrophages (M2 TAMs), N2 tumor-associated neutrophils (N2 TANs), myeloid-derived suppressor cells (MDSCs), effector regulatory T cells (eTregs), and regulatory B cells (Bregs) in the tumor microenvironment and reprogram TAMs and TANs into tumor killer cells. The most widely used immunotherapy strategies are the immune checkpoint inhibitor programmed cell death 1/programmed death-ligand 1 (PD-1/PD-L1) antibody, cytotoxic T lymphocyte–associated protein 4 (CTLA-4) antibody, and chimeric antigen receptor T (CAR-T) in ACT, and these therapeutic strategies have significant anti-tumor efficacy in solid tumors and hematological tumors. Targeting other immune cells provides a new direction for the immunotherapy of GC despite the relatively weak clinical data, which have been confirmed to restore or enhance anti-tumor immune function in preclinical studies and some treatment strategies have entered the clinical trial stage, and it is expected that more and more effective immune cell–based therapeutic methods will be developed and applied.
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Affiliation(s)
- Yan Zhao
- Department of Oncology and Hematology, China-Japan Union Hospital of Jilin University, Changchun, China
| | - Yuansong Bai
- Department of Oncology and Hematology, China-Japan Union Hospital of Jilin University, Changchun, China
| | - Meili Shen
- Department of Radiation Oncology, China-Japan Union Hospital of Jilin University, Changchun, China
- *Correspondence: Yapeng Li, ; Meili Shen,
| | - Yapeng Li
- The National and Local Joint Engineering Laboratory for Synthesis Technology of High Performance Polymer, College of Chemistry, Jilin University, Changchun, China
- *Correspondence: Yapeng Li, ; Meili Shen,
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15
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Wang Y, Fang C, Chen R, Yuan S, Chen L, Qiu X, Qian X, Zhang X, Xiao Z, Wang Q, Fu B, Song X, Li Y. rhG-CSF is associated with an increased risk of metastasis in NSCLC patients following postoperative chemotherapy. BMC Cancer 2022; 22:741. [PMID: 35799161 PMCID: PMC9261064 DOI: 10.1186/s12885-022-09850-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/05/2021] [Accepted: 06/30/2022] [Indexed: 11/11/2022] Open
Abstract
Background Recombinant human granulocyte colony-stimulating factor (rhG-CSF) reduces neutropenia events and is widely used in cancer patients receiving chemotherapy. However, the effects of rhG-CSF on distant organ metastasis (DOM) in non-small-cell lung cancer (NSCLC) patients following postoperative chemotherapy are not clear. Methods A retrospective cohort study was performed on NSCLC patients who underwent complete surgical resection and postoperative systemic chemotherapy at The First Affiliated Hospital of Nanchang University between 1 January 2012 and 31 December 2017. The effect of rhG-CSF on DOM was assessed with other confounding factors using Cox regression analyses. Results We identified 307 NSCLC patients who received postoperative systemic chemotherapy (n = 246 in the rhG-CSF group, n = 61 in the No rhG-CSF group). The incidence of DOM in postoperative NSCLC patients with rhG-CSF treatment was observably higher than in patients without rhG-CSF treatment (48.3% vs. 27.9%, p < 0.05). Univariate regression analysis revealed that rhG-CSF and pathological stage were independent risk factors for metastasis-free survival (MFS) (p < 0.05). RhG-CSF users had a higher risk of DOM (adjusted HR: 2.33, 95% CI: 1.31–4.15) than nonusers of rhG-CSF. The association between rhG-CSF and the risk of DOM was significant only in patients presenting with myelosuppression (HR: 3.34, 95% CI: 1.86–6.02) and not in patients without myelosuppression (HR: 0.71, 95% CI: 0.17–2.94, Interaction p-value< 0.01). The risk increased with higher dose density of rhG-CSF compared to rhG-CSF versus no users (p for trend< 0.001). Conclusion These analyses indicate that rhG-CSF use is related to DOM following postoperative chemotherapy in NSCLC.
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Affiliation(s)
- Yong Wang
- Department of Medical Oncology, The First Affiliated Hospital of Nanchang University, 17 Yongwai Zheng Road, Nanchang, 330000, China.,Medical Innovation Center, The First Affiliated Hospital of Nanchang University, 17 Yongwai Zheng Road, Nanchang, 330000, China
| | - Chen Fang
- Department of Medical Oncology, The First Affiliated Hospital of Nanchang University, 17 Yongwai Zheng Road, Nanchang, 330000, China.,Medical Innovation Center, The First Affiliated Hospital of Nanchang University, 17 Yongwai Zheng Road, Nanchang, 330000, China
| | - Renfang Chen
- Department of Medical Oncology, The First Affiliated Hospital of Nanchang University, 17 Yongwai Zheng Road, Nanchang, 330000, China.,Medical Innovation Center, The First Affiliated Hospital of Nanchang University, 17 Yongwai Zheng Road, Nanchang, 330000, China
| | - Shangkun Yuan
- Department of Medical Oncology, The First Affiliated Hospital of Nanchang University, 17 Yongwai Zheng Road, Nanchang, 330000, China.,Medical Innovation Center, The First Affiliated Hospital of Nanchang University, 17 Yongwai Zheng Road, Nanchang, 330000, China
| | - Lin Chen
- Department of Internal Neurology, The Second Affiliated Hospital of Nanchang University, 1 MingDe Road, Nanchang, 330000, China
| | - Xiaotong Qiu
- Department of Medical Oncology, The First Affiliated Hospital of Nanchang University, 17 Yongwai Zheng Road, Nanchang, 330000, China
| | - Xiaoying Qian
- Department of Medical Oncology, The First Affiliated Hospital of Nanchang University, 17 Yongwai Zheng Road, Nanchang, 330000, China.,Medical Innovation Center, The First Affiliated Hospital of Nanchang University, 17 Yongwai Zheng Road, Nanchang, 330000, China
| | - Xinwei Zhang
- Department of Medical Oncology, The First Affiliated Hospital of Nanchang University, 17 Yongwai Zheng Road, Nanchang, 330000, China
| | - Zhehao Xiao
- Department of Medical Oncology, The First Affiliated Hospital of Nanchang University, 17 Yongwai Zheng Road, Nanchang, 330000, China
| | - Qian Wang
- Department of Medical Oncology, The First Affiliated Hospital of Nanchang University, 17 Yongwai Zheng Road, Nanchang, 330000, China
| | - Biqi Fu
- Department of Rheumatology, The First Affiliated Hospital of Nanchang University, 17 Yongwai Zheng Road, Nanchang, 330000, China
| | - Xiaoling Song
- Department of Medical Record Room, The First Affiliated Hospital of Nanchang University, 17 Yongwai Zheng Road, Nanchang, 330000, China
| | - Yong Li
- Department of Medical Oncology, The First Affiliated Hospital of Nanchang University, 17 Yongwai Zheng Road, Nanchang, 330000, China. .,Medical Innovation Center, The First Affiliated Hospital of Nanchang University, 17 Yongwai Zheng Road, Nanchang, 330000, China.
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Matsumoto Y, Ayani N, Omichi C, Oya N, Matsuoka T, Kobayashi T, Kuroda J, Narumoto J. Diagnostic error regarding the cause of cytopenia when increasing psychotropic drugs: Two case reports. Asian J Psychiatr 2022; 67:102952. [PMID: 34891065 DOI: 10.1016/j.ajp.2021.102952] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/30/2021] [Revised: 11/24/2021] [Accepted: 11/28/2021] [Indexed: 11/26/2022]
Abstract
Several psychotropic drugs can cause cytopenia, especially after increasing dosages or initiating treatment. However, cytopenia in patients with psychiatric disorders can also be due to other conditions such as leukemia. In this report, we discuss two cases of cytopenia that occurred during the adjustment of psychotropic medications in patients with severe psychiatric illness. The initial diagnosis in each case was drug-induced cytopenia; however, later, the cause of cytopenia was found to be acute promyelocytic leukemia. When cytopenia is observed while increasing the dosage of psychotropic drugs, suspicious drugs should be discontinued, though the possibility that cytopenia could be due to other reasons should be considered. If there are no signs of recovering blood cells or if cytopenia is severe, psychiatrists should consult hematologists promptly.
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Affiliation(s)
- Yoshihiro Matsumoto
- Department of Psychiatry, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, 465 Kajii-cho, Kawaramachi-Hirokoji, Kamigyo-ku, Kyoto 602-8566, Japan
| | - Nobutaka Ayani
- Department of Psychiatry, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, 465 Kajii-cho, Kawaramachi-Hirokoji, Kamigyo-ku, Kyoto 602-8566, Japan; Department of Psychiatry, National Hospital Organization, Maizuru Medical Center, 2410 Yukinaga, Maizuru, Kyoto 625-8502, Japan.
| | - Chie Omichi
- Department of Psychiatry, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, 465 Kajii-cho, Kawaramachi-Hirokoji, Kamigyo-ku, Kyoto 602-8566, Japan; Department of Psychiatry, Shiga University of Medical Science, Tsukinowa-cho, Seta, Otsu, Shiga 520-2192, Japan
| | - Nozomu Oya
- Department of Psychiatry, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, 465 Kajii-cho, Kawaramachi-Hirokoji, Kamigyo-ku, Kyoto 602-8566, Japan
| | - Teruyuki Matsuoka
- Department of Psychiatry, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, 465 Kajii-cho, Kawaramachi-Hirokoji, Kamigyo-ku, Kyoto 602-8566, Japan
| | - Tsutomu Kobayashi
- Division of Hematology and Oncology, Department of Medicine, Kyoto Prefectural University of Medicine Graduate School of Medical Science, 465 Kajii-cho, Kawaramachi-Hirokoji, Kamigyo-ku, Kyoto 602-8566, Japan
| | - Junya Kuroda
- Division of Hematology and Oncology, Department of Medicine, Kyoto Prefectural University of Medicine Graduate School of Medical Science, 465 Kajii-cho, Kawaramachi-Hirokoji, Kamigyo-ku, Kyoto 602-8566, Japan
| | - Jin Narumoto
- Department of Psychiatry, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, 465 Kajii-cho, Kawaramachi-Hirokoji, Kamigyo-ku, Kyoto 602-8566, Japan
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Tamura K, Ishigaki K, Iizuka K, Nagumo T, Yoshida O, Asano K. Neutrophilic leucocytosis induced by granulocyte colony-stimulating factor and interleukin-6 in canine primary lung adenocarcinoma. Vet Med Sci 2021; 8:483-491. [PMID: 34935301 PMCID: PMC8959335 DOI: 10.1002/vms3.694] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022] Open
Abstract
Background Neutrophilic leucocytosis as a paraneoplastic syndrome may occur in dogs with lymphoma, renal carcinoma, rectal polyps and metastatic fibrosarcoma. However, the information on canine lung adenocarcinoma with neutrophilic leucocytosis is lacking. Objective This study aimed to describe the clinical features and cytokine profiles of canine patients with primary lung adenocarcinoma and neutrophilic leucocytosis. Methods Two dogs (cases #1 and #2), each with a solitary lung adenocarcinoma, were included. Both cases had leucocytosis and underwent lung lobectomy. The resected tumours were analysed for the expression of granulocyte colony‐stimulating factor (G‐CSF), granulocyte macrophage colony‐stimulating factor (GM‐CSF) and interleukin‐6 (IL6) by quantitative real‐time PCR compared with normal lung tissues. Results At the initial examination, neither patient had any clinical signs or fever. White blood cell count (WBC) was 58,300/μl and 32,900/μl in cases #1 and #2, respectively. The gene expression of G‐CSF increased 6.7‐and 19.7‐fold in cases #1 and #2, respectively. The gene expression of IL6 markedly increased (30‐fold) in case #1, whereas it increased slightly (1.9‐fold) in case #2. On the other hand, that of GM‐CSF was slightly changed in both cases. The WBC count postoperatively decreased to within the normal range in both cases. The postoperative survival times were 347 and 118 days in cases #1 and #2, respectively. Conclusions This study describes G‐CSF and IL6 producing lung adenocarcinoma associated with neutrophilic leucocytosis in dogs. Canine patients with pulmonary adenocarcinomas that have elevated G‐CSF and IL6 levels may have a guarded prognosis. Further investigations are needed to clarify the prognosis of canine cytokine‐producing lung adenocarcinoma.
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Affiliation(s)
- Kei Tamura
- Laboratory of Veterinary SurgeryDepartment of Veterinary MedicineCollege of Bioresource SciencesNihon UniversityFujisawaKanagawaJapan
| | - Kumiko Ishigaki
- Laboratory of Veterinary SurgeryDepartment of Veterinary MedicineCollege of Bioresource SciencesNihon UniversityFujisawaKanagawaJapan
| | - Keigo Iizuka
- Laboratory of Veterinary SurgeryDepartment of Veterinary MedicineCollege of Bioresource SciencesNihon UniversityFujisawaKanagawaJapan
| | - Takahiro Nagumo
- Laboratory of Veterinary SurgeryDepartment of Veterinary MedicineCollege of Bioresource SciencesNihon UniversityFujisawaKanagawaJapan
| | - Orie Yoshida
- Laboratory of Veterinary SurgeryDepartment of Veterinary MedicineCollege of Bioresource SciencesNihon UniversityFujisawaKanagawaJapan
| | - Kazushi Asano
- Laboratory of Veterinary SurgeryDepartment of Veterinary MedicineCollege of Bioresource SciencesNihon UniversityFujisawaKanagawaJapan
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18
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Mittmann LA, Haring F, Schaubächer JB, Hennel R, Smiljanov B, Zuchtriegel G, Canis M, Gires O, Krombach F, Holdt L, Brandau S, Vogl T, Lauber K, Uhl B, Reichel CA. Uncoupled biological and chronological aging of neutrophils in cancer promotes tumor progression. J Immunother Cancer 2021; 9:jitc-2021-003495. [PMID: 34876407 PMCID: PMC8655594 DOI: 10.1136/jitc-2021-003495] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 11/04/2021] [Indexed: 01/13/2023] Open
Abstract
Background Beyond their fundamental role in homeostasis and host defense, neutrophilic granulocytes (neutrophils) are increasingly recognized to contribute to the pathogenesis of malignant tumors. Recently, aging of mature neutrophils in the systemic circulation has been identified to be critical for these immune cells to properly unfold their homeostatic and anti-infectious functional properties. The role of neutrophil aging in cancer remains largely obscure. Methods Employing advanced in vivo microscopy techniques in different animal models of cancer as well as utilizing pulse-labeling and cell transfer approaches, various ex vivo/in vitro assays, and human data, we sought to define the functional relevance of neutrophil aging in cancer. Results Here, we show that signals released during early tumor growth accelerate biological aging of circulating neutrophils, hence uncoupling biological from chronological aging of these immune cells. This facilitates the accumulation of highly reactive neutrophils in malignant lesions and endows them with potent protumorigenic functions, thus promoting tumor progression. Counteracting uncoupled biological aging of circulating neutrophils by blocking the chemokine receptor CXCR2 effectively suppressed tumor growth. Conclusions Our data uncover a self-sustaining mechanism of malignant neoplasms in fostering protumorigenic phenotypic and functional changes in circulating neutrophils. Interference with this aberrant process might therefore provide a novel, already pharmacologically targetable strategy for cancer immunotherapy.
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Affiliation(s)
- Laura A Mittmann
- Department of Otorhinolaryngology, LMU München, Munich, Germany.,Walter Brendel Centre of Experimental Medicine, LMU München, Munich, Germany
| | - Florian Haring
- Department of Otorhinolaryngology, LMU München, Munich, Germany.,Walter Brendel Centre of Experimental Medicine, LMU München, Munich, Germany
| | - Johanna B Schaubächer
- Department of Otorhinolaryngology, LMU München, Munich, Germany.,Walter Brendel Centre of Experimental Medicine, LMU München, Munich, Germany
| | - Roman Hennel
- Department of Radiotherapy and Radiation Oncology, LMU München, Munich, Germany
| | - Bojan Smiljanov
- Department of Otorhinolaryngology, LMU München, Munich, Germany.,Walter Brendel Centre of Experimental Medicine, LMU München, Munich, Germany
| | - Gabriele Zuchtriegel
- Department of Otorhinolaryngology, LMU München, Munich, Germany.,Walter Brendel Centre of Experimental Medicine, LMU München, Munich, Germany
| | - Martin Canis
- Department of Otorhinolaryngology, LMU München, Munich, Germany
| | - Olivier Gires
- Department of Otorhinolaryngology, LMU München, Munich, Germany
| | - Fritz Krombach
- Walter Brendel Centre of Experimental Medicine, LMU München, Munich, Germany
| | - Lesca Holdt
- Institute for Laboratory Medicine, LMU München, Munich, Germany
| | - Sven Brandau
- Department of Otorhinolaryngology, University Hospital Essen, Essen, Germany
| | - Thomas Vogl
- Institute for Immunology, University of Munster, Munster, Germany
| | - Kirsten Lauber
- Department of Radiotherapy and Radiation Oncology, LMU München, Munich, Germany
| | - Bernd Uhl
- Department of Otorhinolaryngology, LMU München, Munich, Germany.,Walter Brendel Centre of Experimental Medicine, LMU München, Munich, Germany
| | - Christoph A Reichel
- Department of Otorhinolaryngology, LMU München, Munich, Germany .,Walter Brendel Centre of Experimental Medicine, LMU München, Munich, Germany
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19
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Mouchemore KA, Anderson RL. Immunomodulatory effects of G-CSF in cancer: Therapeutic implications. Semin Immunol 2021; 54:101512. [PMID: 34763974 DOI: 10.1016/j.smim.2021.101512] [Citation(s) in RCA: 29] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/02/2021] [Accepted: 10/23/2021] [Indexed: 01/04/2023]
Abstract
Numerous preclinical studies have reported a pro-tumour role for granulocyte colony-stimulating factor (G-CSF) that is predominantly mediated by neutrophils and MDSCs, the major G-CSF receptor expressing populations. In the presence of G-CSF (either tumour-derived or exogenous) these myeloid populations commonly exhibit a T cell suppressive phenotype. However, the direct effects of this cytokine on other immune lineages, such as T and NK cells, are not as well established. Herein we discuss the most recent data relating to the effect of G-CSF on the major immune populations, exclusively in the context of cancer. Recent publications have drawn attention to the other tumour-promoting effects of G-CSF on myeloid cells, including NETosis, promotion of cancer stemness and skewed differentiation of bone marrow progenitors towards myelopoiesis. Although G-CSF is safely and commonly used as a supportive therapy to prevent or treat chemotherapy-associated neutropenia in cancer patients, we also discuss the potential impacts of G-CSF on other anti-cancer treatments. Importantly, considerations for immune checkpoint blockade are highlighted, as many publications report a T cell suppressive effect of G-CSF that may diminish the effectiveness of this immunotherapy.
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Affiliation(s)
- Kellie A Mouchemore
- Olivia Newton-John Cancer Research Institute, Heidelberg, VIC 3084, Australia; School of Cancer Medicine, La Trobe University, Bundoora, VIC 3086, Australia
| | - Robin L Anderson
- Olivia Newton-John Cancer Research Institute, Heidelberg, VIC 3084, Australia; School of Cancer Medicine, La Trobe University, Bundoora, VIC 3086, Australia; Sir Peter MacCallum Department of Oncology, University of Melbourne, Parkville, VIC, Australia.
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20
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Hiraga T, Ito S, Mizoguchi T. Opposing Effects of Granulocyte Colony-Stimulating Factor on the Initiation and Progression of Breast Cancer Bone Metastases. Mol Cancer Res 2021; 19:2110-2119. [PMID: 34465584 DOI: 10.1158/1541-7786.mcr-21-0243] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/02/2021] [Revised: 07/09/2021] [Accepted: 08/27/2021] [Indexed: 11/16/2022]
Abstract
Granulocyte colony stimulating factor (G-CSF), an essential cytokine regulating granulopoiesis, is expressed in a substantial proportion of breast cancers, and it has been implicated in cancer progression. Here, we examined effects of G-CSF on the development of bone metastases of breast cancer using immunocompetent mouse models. The expression of CXC chemokine ligand 12 (CXCL12) in bone marrow stromal cells, which plays a critical role in the maintenance of hematopoietic stem cells and also in cancer cell homing to bone, was markedly decreased in mice treated with G-CSF. Flow cytometric analysis revealed that pretreatment of mice with G-CSF reduced the number of bone-homing cancer cells. G-CSF also increased the population of myeloid-derived suppressor cells (MDSCs) in bone marrow. Depletion of MDSCs using anti-Gr-1 antibody treatment significantly decreased the metastatic tumor burden in bone. The overall effects of G-CSF on bone metastases were finally examined using two different treatment protocols. When mice were treated with G-CSF prior to the tumor cell inoculation, G-CSF did not change bone metastatic-tumor burden. In contrast, when G-CSF treatment was started after the tumor cells had homed to bone, G-CSF significantly accelerated bone metastases formation. These results suggest that G-CSF suppressed cancer cell homing to bone by downregulating CXCL12 expression in bone marrow stromal cells, whereas G-CSF stimulated the progression of bone metastases at least in part by MDSC-mediated mechanisms. IMPLICATIONS: G-CSF had opposing effects on the initiation and progression of bone metastases of breast cancer and the balance may regulate the metastatic tumor burden.
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Affiliation(s)
- Toru Hiraga
- Department of Histology and Cell Biology, Matsumoto Dental University, Shiojiri-shi, Nagano, Japan.
| | - Susumu Ito
- Division of Instrumental Analysis, Research Center for Human and Environmental Sciences, Shinshu University, Matsumoto-shi, Nagano, Japan
| | - Toshihide Mizoguchi
- Institute for Oral Science, Matsumoto Dental University, Shiojiri-shi, Nagano, Japan.,Oral Health Science Center, Tokyo Dental College, Chiyoda-ku, Tokyo, Japan
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21
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Granulocyte Colony Stimulating Factor Expression in Breast Cancer and Its Association with Carbonic Anhydrase IX and Immune Checkpoints. Cancers (Basel) 2021; 13:cancers13051022. [PMID: 33804486 PMCID: PMC7957699 DOI: 10.3390/cancers13051022] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/08/2021] [Revised: 02/10/2021] [Accepted: 02/23/2021] [Indexed: 01/15/2023] Open
Abstract
Simple Summary Preclinical studies suggest that interactions between granulocyte colony-stimulating factor (G-CSF) and hypoxia-induced carbonic anhydrase IX regulate the trafficking and function of immune cells in the tumour microenvironment. We investigated the clinical significance of this crosstalk by analyzing the protein expression of G-CSF and macrophage markers by immunohistochemistry on a well-characterized tissue microarray series of invasive breast cancers. We report that high expression of G-CSF on breast carcinoma cells is linked with significantly improved survival in an important group of breast cancers that do not respond to hormonal therapy. These tumours were infiltrated by immune cells expressing biomarkers that can be targeted with immune checkpoint inhibitor drugs. In contrast, carbonic anhydrase IX expression was associated with unfavourable outcomes. Abstract Purpose: Granulocyte colony-stimulating factor (G-CSF) and hypoxia modulate the tumour immune microenvironment. In model systems, hypoxia-induced carbonic anhydrase IX (CAIX) has been associated with G-CSF and immune responses, including M2 polarization of macrophages. We investigated whether these associations exist in human breast cancer specimens, their relation to breast cancer subtypes, and clinical outcome. Methods: Using validated protocols and prespecified scoring methodology, G-CSF expression on carcinoma cells and CD163 expression on tumour-associated macrophages were assayed by immunohistochemistry and applied to a tissue microarray series of 2960 primary excision specimens linked to clinicopathologic, biomarker, and outcome data. Results: G-CSFhigh expression showed a significant positive association with ER negativity, HER2 positivity, presence of CD163+ M2 macrophages, and CAIX expression. In univariate analysis, G-CSFhigh phenotype was associated with improved survival in non-luminal cases, although the CAIX+ subset had a significantly adverse prognosis. A significant positive association was observed between immune checkpoint biomarkers on tumour-infiltrating lymphocytes and both G-CSF- and CAIX-expressing carcinoma cells. Immune checkpoint biomarkers correlated significantly with favourable prognosis in G-CSFhigh/non-luminal cases independent of standard clinicopathological features. Conclusions: The prognostic associations linking G-CSF to immune biomarkers and CAIX strongly support their immunomodulatory roles in the tumour microenvironment.
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22
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Theron AJ, Steel HC, Rapoport BL, Anderson R. Contrasting Immunopathogenic and Therapeutic Roles of Granulocyte Colony-Stimulating Factor in Cancer. Pharmaceuticals (Basel) 2020; 13:ph13110406. [PMID: 33233675 PMCID: PMC7699711 DOI: 10.3390/ph13110406] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/02/2020] [Revised: 11/16/2020] [Accepted: 11/16/2020] [Indexed: 12/15/2022] Open
Abstract
Tumor cells are particularly adept at exploiting the immunosuppressive potential of neutrophils as a strategy to achieve uncontrolled proliferation and spread. Recruitment of neutrophils, particularly those of an immature phenotype, known as granulocytic myeloid-derived suppressor cells, is achieved via the production of tumor-derived granulocyte colony-stimulating factor (G-CSF) and neutrophil-selective chemokines. This is not the only mechanism by which G-CSF contributes to tumor-mediated immunosuppression. In this context, the G-CSF receptor is expressed on various cells of the adaptive and innate immune systems and is associated with induction of T cell polarization towards the Th2 and regulatory T cell (Treg) phenotypes. In contrast to the potentially adverse effects of sustained, endogenous production of G-CSF by tumor cells, stringently controlled prophylactic administration of recombinant (r) G-CSF is now a widely practiced strategy in medical oncology to prevent, and in some cases treat, chemotherapy-induced severe neutropenia. Following an overview of the synthesis, structure and function of G-CSF and its receptor, the remainder of this review is focused on: (i) effects of G-CSF on the cells of the adaptive and innate immune systems; (ii) mechanisms by which this cytokine promotes tumor progression and invasion; and (iii) current clinical applications and potential risks of the use of rG-CSF in medical oncology.
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Affiliation(s)
- Annette J. Theron
- Department of Immunology, Faculty of Health Sciences, University of Pretoria, Pretoria 0001, South Africa; (H.C.S.); (B.L.R.); (R.A.)
- Correspondence: ; Tel.: +27-12-319-2355
| | - Helen C. Steel
- Department of Immunology, Faculty of Health Sciences, University of Pretoria, Pretoria 0001, South Africa; (H.C.S.); (B.L.R.); (R.A.)
| | - Bernardo L. Rapoport
- Department of Immunology, Faculty of Health Sciences, University of Pretoria, Pretoria 0001, South Africa; (H.C.S.); (B.L.R.); (R.A.)
- The Medical Oncology Centre of Rosebank, Johannesburg 2196, South Africa
| | - Ronald Anderson
- Department of Immunology, Faculty of Health Sciences, University of Pretoria, Pretoria 0001, South Africa; (H.C.S.); (B.L.R.); (R.A.)
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23
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Chen B, Wang D, Bian Y, Li J, Yang T, Li N, Qiao C. Systematic Identification of Hub Genes in Placenta Accreta Spectrum Based on Integrated Transcriptomic and Proteomic Analysis. Front Genet 2020; 11:551495. [PMID: 33101378 PMCID: PMC7522549 DOI: 10.3389/fgene.2020.551495] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/13/2020] [Accepted: 08/25/2020] [Indexed: 12/13/2022] Open
Abstract
Placenta accreta spectrum (PAS) is a pathological condition of the placenta with abnormal adhesion or invasion of the placental villi to the uterine wall, which is associated with a variety of adverse maternal and fetal outcomes. Although some PAS-related molecules have been reported, the underlying regulatory mechanism is still unclear. Compared with the study of single gene or pathway, omics study, using advanced sequencing technology and bioinformatics methods, can increase our systematic understanding of diseases. In this study, placenta tissues from 5 patients with PAS and 5 healthy pregnant women were collected for transcriptomic and proteomic sequencing and integrated analysis. A total of 728 messenger RNAs and 439 proteins were found to be significantly different between PAS group and non-PAS group, in which 23 hub genes were differentially expressed in both transcriptome and proteome. Functional enrichment analysis showed that the differentially expressed genes were mainly related to cell proliferation, migration and vascular development. Totally 18 long non-coding RNA were found that might regulate the expression of hub genes. Many kinds of single nucleotide polymorphism, alternative splicing and gene fusion of hub genes were detected. This is the first time to systematically explore the hub genes and gene structure variations of PAS through integrated omics analysis, which provided a genetic basis for further in-depth study on the underlying regulatory mechanism of PAS.
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Affiliation(s)
- Bingnan Chen
- Department of Obstetrics and Gynecology, Shengjing Hospital of China Medical University, Shenyang, China.,Key Laboratory of Maternal-Fetal Medicine of Liaoning Province, China Medical University, Shenyang, China.,Key Laboratory of Obstetrics and Gynecology of Higher Education of Liaoning Province, Shenyang, China.,Research Center of China Medical University Birth Cohort, Shenyang, China
| | - Di Wang
- Department of Internal Medicine, Shengjing Hospital of China Medical University, Shenyang, China
| | - Yue Bian
- Department of Obstetrics and Gynecology, Shengjing Hospital of China Medical University, Shenyang, China.,Key Laboratory of Maternal-Fetal Medicine of Liaoning Province, China Medical University, Shenyang, China.,Key Laboratory of Obstetrics and Gynecology of Higher Education of Liaoning Province, Shenyang, China.,Research Center of China Medical University Birth Cohort, Shenyang, China
| | - Jiapo Li
- Department of Obstetrics and Gynecology, Shengjing Hospital of China Medical University, Shenyang, China.,Key Laboratory of Maternal-Fetal Medicine of Liaoning Province, China Medical University, Shenyang, China.,Key Laboratory of Obstetrics and Gynecology of Higher Education of Liaoning Province, Shenyang, China.,Research Center of China Medical University Birth Cohort, Shenyang, China
| | - Tian Yang
- Department of Obstetrics and Gynecology, Shengjing Hospital of China Medical University, Shenyang, China.,Key Laboratory of Maternal-Fetal Medicine of Liaoning Province, China Medical University, Shenyang, China.,Key Laboratory of Obstetrics and Gynecology of Higher Education of Liaoning Province, Shenyang, China.,Research Center of China Medical University Birth Cohort, Shenyang, China
| | - Na Li
- Department of Obstetrics and Gynecology, Shengjing Hospital of China Medical University, Shenyang, China.,Key Laboratory of Maternal-Fetal Medicine of Liaoning Province, China Medical University, Shenyang, China.,Key Laboratory of Obstetrics and Gynecology of Higher Education of Liaoning Province, Shenyang, China.,Research Center of China Medical University Birth Cohort, Shenyang, China
| | - Chong Qiao
- Department of Obstetrics and Gynecology, Shengjing Hospital of China Medical University, Shenyang, China.,Key Laboratory of Maternal-Fetal Medicine of Liaoning Province, China Medical University, Shenyang, China.,Key Laboratory of Obstetrics and Gynecology of Higher Education of Liaoning Province, Shenyang, China.,Research Center of China Medical University Birth Cohort, Shenyang, China
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24
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Doblinger N, Gruber M, Ahrens N. Granulozytentransfusion: Update 2020. TRANSFUSIONSMEDIZIN 2020. [DOI: 10.1055/a-1090-0369] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/23/2022]
Abstract
ZusammenfassungDie therapeutische Anwendung von Granulozytenkonzentraten erfolgt im klinischen Alltag im Gegensatz zu der anderer Blutprodukte nur selten und unregelmäßig. Der zurückhaltende Einsatz beruht unter anderem auf dem Fehlen einer breiten Evidenz, logistischen und wirtschaftlichen Problemen und dem Vorhandensein anderer potenter Therapieoptionen neutropener Infektionen. Dennoch gab es in den letzten Jahren neue wissenschaftliche Erkenntnisse nicht nur zu Physiologie und Pathophysiologie der Granulozyten, wie neu charakterisierten zellulären Verteidigungsstrategien oder deren Mitwirkung bei thrombotischen oder malignen Ereignissen, sondern auch zu deren therapeutischem Effekt. Dieser wird von einer Vielzahl an Parametern, wie der Art der Infektion, dem Transfusionszeitpunkt und der Dosis, beeinflusst. Das macht die Indikationsstellung zu einer komplexen Einzelfallentscheidung und es gilt, die heterogene Datenlage systematisch zusammenzufassen. Außerdem wurden die etablierten
Indikationen neutropener bzw. neutropathischer Infektionen um experimentelle, mögliche neue Anwendungsgebiete wie die Mukositis oder Leukämiebehandlung erweitert. Die erfolgreiche Anwendung setzt eine geeignete, moderne Herstellungsweise voraus. Neben der Apherese, bei der eine relativ hohe Spenderbelastung unter anderem durch Nebenwirkungen von Mobilisationsregime und Sedimentationsbeschleunigern berücksichtigt werden muss, existieren weitere Verfahren wie die Gewinnung von Granulozyten aus Buffy Coats von Vollblutspenden. Diese versprechen eine Reduktion logistischer Probleme und unerwünschter Wirkungen auf den Spender. Unerwünschte Wirkungen bei Empfängern von Granulozytentransfusionen sollten nach wie vor berücksichtigt und gegen einen erhofften therapeutischen Effekt abgewogen werden.
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Affiliation(s)
- Nina Doblinger
- Klinik für Anästhesiologie, Universitätsklinikum Regensburg
| | - Michael Gruber
- Klinik für Anästhesiologie, Universitätsklinikum Regensburg
| | - Norbert Ahrens
- Institut für Klinische Chemie und Laboratoriumsmedizin, Universitätsklinikum Regensburg
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25
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Mukaida N, Sasaki SI, Baba T. Two-Faced Roles of Tumor-Associated Neutrophils in Cancer Development and Progression. Int J Mol Sci 2020; 21:3457. [PMID: 32422991 PMCID: PMC7278934 DOI: 10.3390/ijms21103457] [Citation(s) in RCA: 56] [Impact Index Per Article: 11.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/24/2020] [Revised: 05/11/2020] [Accepted: 05/13/2020] [Indexed: 02/07/2023] Open
Abstract
Neutrophils are the most abundant circulating leukocytes in humans. Neutrophil infiltration into tumor tissues has long been observed but its roles have been ignored due to the presumed short life cycle and metabolic incompetence of neutrophils. Recent advances in neutrophil biology research have revealed that neutrophils have a longer life cycle with a potential to express various bioactive molecules. Clinical studies have simultaneously unraveled an increase in the neutrophil-lymphocyte ratio (NLR), a ratio of absolute neutrophil to absolute lymphocyte numbers in cancer patient peripheral blood and an association of higher NLR with more advanced or aggressive disease. As a consequence, tumor-associated neutrophils (TANs) have emerged as important players in tumor microenvironment. The elucidation of the roles of TANs, however, has been hampered by their multitude of plasticity in terms of phenotypes and functionality. Difficulties are further enhanced by the presence of a related cell population-polymorphonuclear leukocyte (PMN)-myeloid-derived suppressor cells (MDSCs)-and various dissimilar aspects of neutrophil biology between humans and mice. Here, we discuss TAN biology in various tumorigenesis processes, and particularly focus on the context-dependent functional heterogeneity of TANs.
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Affiliation(s)
- Naofumi Mukaida
- Division of Molecular Bioregulation, Cancer Research Institute, Kanazawa University, Kakuma-machi, Kanazawa, Ishikawa 920-1192, Japan; (S.-i.S.); (T.B.)
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26
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Lecot P, Sarabi M, Pereira Abrantes M, Mussard J, Koenderman L, Caux C, Bendriss-Vermare N, Michallet MC. Neutrophil Heterogeneity in Cancer: From Biology to Therapies. Front Immunol 2019; 10:2155. [PMID: 31616408 PMCID: PMC6764113 DOI: 10.3389/fimmu.2019.02155] [Citation(s) in RCA: 86] [Impact Index Per Article: 14.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/20/2019] [Accepted: 08/28/2019] [Indexed: 12/12/2022] Open
Abstract
Neutrophils have been extensively described in the pathophysiology of autoimmune and infectious diseases. Accumulating evidence also suggests the important role of neutrophils in cancer progression through their interaction with cancer and immune cells in blood and in the tumor microenvironment (TME). Most studies have described neutrophils as key drivers of cancer progression, due to their involvement in various tumor promoting functions including proliferation, aggressiveness, and dissemination, as well as in immune suppression. However, such studies were focusing on late-stages of tumorigenesis, in which chronic inflammation had already developed. The role of tumor-associated neutrophils (TANs) at early stages of tumor development remains poorly described, though recent findings indicate that early-stage TANs may display anti-tumor properties. Beyond their role at tumor site, evidence supported by NLR retrospective studies and functional analyses suggest that blood neutrophils could also actively contribute to tumorigenesis. Hence, it appears that the phenotype and functions of neutrophils vary greatly during tumor progression, highlighting their heterogeneity. The origin of pro- or anti-tumor neutrophils is generally believed to arise following a change in cell state, from resting to activated. Moreover, the fate of neutrophils may also involve distinct differentiation programs yielding various subsets of pro or anti-tumor neutrophils. In this review, we will discuss the current knowledge on neutrophils heterogeneity across different tissues and their impact on tumorigenesis, as well as neutrophil-based therapeutic strategies that have shown promising results in pre-clinical studies, paving the way for the design of neutrophil-based next generation immunotherapy.
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Affiliation(s)
- Pacôme Lecot
- Department of Immunity, Virus, and Inflammation (IVI), Centre de Recherche en Cancérologie de Lyon, Centre Léon Bérard, University of Lyon, Université Claude Bernard Lyon 1, INSERM 1052, CNRS 5286, Lyon, France
| | - Matthieu Sarabi
- Department of Immunity, Virus, and Inflammation (IVI), Centre de Recherche en Cancérologie de Lyon, Centre Léon Bérard, University of Lyon, Université Claude Bernard Lyon 1, INSERM 1052, CNRS 5286, Lyon, France
| | - Manuela Pereira Abrantes
- Department of Immunity, Virus, and Inflammation (IVI), Centre de Recherche en Cancérologie de Lyon, Centre Léon Bérard, University of Lyon, Université Claude Bernard Lyon 1, INSERM 1052, CNRS 5286, Lyon, France
| | - Julie Mussard
- Department of Immunity, Virus, and Inflammation (IVI), Centre de Recherche en Cancérologie de Lyon, Centre Léon Bérard, University of Lyon, Université Claude Bernard Lyon 1, INSERM 1052, CNRS 5286, Lyon, France
| | - Leo Koenderman
- Department of Respiratory Medicine and Center of Translational Immunology, University Medical Center Utrecht, Utrecht, Netherlands
| | - Christophe Caux
- Department of Immunity, Virus, and Inflammation (IVI), Centre de Recherche en Cancérologie de Lyon, Centre Léon Bérard, University of Lyon, Université Claude Bernard Lyon 1, INSERM 1052, CNRS 5286, Lyon, France
| | - Nathalie Bendriss-Vermare
- Department of Immunity, Virus, and Inflammation (IVI), Centre de Recherche en Cancérologie de Lyon, Centre Léon Bérard, University of Lyon, Université Claude Bernard Lyon 1, INSERM 1052, CNRS 5286, Lyon, France
| | - Marie-Cécile Michallet
- Department of Immunity, Virus, and Inflammation (IVI), Centre de Recherche en Cancérologie de Lyon, Centre Léon Bérard, University of Lyon, Université Claude Bernard Lyon 1, INSERM 1052, CNRS 5286, Lyon, France
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Novel Aspects of Extracellular Vesicles as Mediators of Cancer-Associated Thrombosis. Cells 2019; 8:cells8070716. [PMID: 31337034 PMCID: PMC6679024 DOI: 10.3390/cells8070716] [Citation(s) in RCA: 43] [Impact Index Per Article: 7.2] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/12/2019] [Revised: 07/09/2019] [Accepted: 07/11/2019] [Indexed: 02/06/2023] Open
Abstract
The establishment of prothrombotic states during cancer progression is well reported but the precise mechanisms underlying this process remain elusive. A number of studies have implicated the presence of the clotting initiator protein, tissue factor (TF), in circulating tumor-derived extracellular vesicles (EVs) with thrombotic manifestations in certain cancer types. Tumor cells, as well as tumor-derived EVs, may activate and promote platelet aggregation by TF-dependent and independent pathways. Cancer cells and their secreted EVs may also facilitate the formation of neutrophil extracellular traps (NETs), which may contribute to thrombus development. Alternatively, the presence of polyphosphate (polyP) in tumor-derived EVs may promote thrombosis through a TF-independent route. We conclude that the contribution of EVs to cancer coagulopathy is quite complex, in which one or more mechanisms may take place in a certain cancer type. In this context, strategies that could attenuate the crosstalk between the proposed pro-hemostatic routes could potentially reduce cancer-associated thrombosis.
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Carvalho É, Hugo de Almeida V, Rondon AMR, Possik PA, Viola JPB, Monteiro RQ. Protease-activated receptor 2 (PAR2) upregulates granulocyte colony stimulating factor (G-CSF) expression in breast cancer cells. Biochem Biophys Res Commun 2018; 504:270-276. [PMID: 30172372 DOI: 10.1016/j.bbrc.2018.08.169] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/19/2018] [Accepted: 08/27/2018] [Indexed: 01/05/2023]
Abstract
Protease-activated receptor 2 (PAR2) is a G-protein coupled receptor which is activated upon cleavage of its N-terminal region. PAR2 has been associated with many aspects regarding tumor progression, such as the production of pro-tumoral cytokines. Granulocyte colony-stimulating factor (G-CSF) is a cytokine essential to neutrophil production and maturation, and it is often overexpressed in tumors. In this study, we evaluated the ability of PAR2 to modulate G-CSF expression. PAR2 and G-CSF were significantly more expressed in metastatic (4T1 and MDA-MB-231) as compared to non-metastatic (67NR and MCF7) breast cancer cell lines. In addition, PAR2 stimulation by a synthetic agonist peptide significantly increased G-CSF gene expression in the metastatic cell lines. Knockdown of PAR2 in 4T1 cells decreased G-CSF expression and secretion. In addition, treatment of 4T1 with the commercial PAR2 antagonist, ENMD-1068, significantly decreased G-CSF expression. cBioPortal analyses of the TCGA database showed a significant co-occurrence of G-CSF and PAR2 gene overexpression in breast cancer samples. In conclusion, our data suggest that PAR2 contributes to G-CSF expression in breast cancer cells, possibly favoring tumor progression.
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Affiliation(s)
- Érika Carvalho
- Institute of Medical Biochemistry Leopoldo de Meis, Federal University of Rio de Janeiro, RJ, Brazil
| | - Vitor Hugo de Almeida
- Institute of Medical Biochemistry Leopoldo de Meis, Federal University of Rio de Janeiro, RJ, Brazil
| | - Araci M R Rondon
- Institute of Medical Biochemistry Leopoldo de Meis, Federal University of Rio de Janeiro, RJ, Brazil
| | - Patricia A Possik
- Program of Cellular Biology, Brazilian National Cancer Institute (INCA), Rio de Janeiro, RJ, Brazil
| | - João P B Viola
- Program of Cellular Biology, Brazilian National Cancer Institute (INCA), Rio de Janeiro, RJ, Brazil
| | - Robson Q Monteiro
- Institute of Medical Biochemistry Leopoldo de Meis, Federal University of Rio de Janeiro, RJ, Brazil.
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Martin OA, Anderson RL. Editorial: Therapy-induced metastasis. Clin Exp Metastasis 2018; 35:219-221. [PMID: 29971590 DOI: 10.1007/s10585-018-9914-x] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/11/2018] [Accepted: 06/18/2018] [Indexed: 12/20/2022]
Abstract
The idea for this Special Issue originated from our recent review in Nature Reviews Clinical Oncology entitled "Does the mobilization of circulating tumour cells during cancer therapy cause metastasis?" Martin et al. (Nat Rev Clin Oncol 14:32-44, 2017). While preparing this review, it became evident that an overwhelming number of preclinical and clinical papers were implicating the involvement of all the major and indispensable cancer treatment modalities in causing increased numbers of tumour cells in circulation (CTCs), and potentially increased risk of distant metastasis. This led to our decision to expand the topic by addressing some of the issues associated with therapy-induced tumour progression. Here, we present papers from ten research groups who give a comprehensive coverage of the biological processes and clinical procedures that can lead to enhanced metastasis and/or tumour recurrence. Our authors provide evidence that all the common therapies, including radiotherapy, chemotherapy, fine needle biopsies, surgical procedures and anaesthesia have the potential to contribute to tumour progression.
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Affiliation(s)
- Olga A Martin
- Peter MacCallum Cancer Centre, Melbourne, VIC, Australia
| | - Robin L Anderson
- Olivia Newton-John Cancer Research Institute, 145 Studley Road, Heidelberg, VIC, Australia. .,La Trobe University School of Cancer Medicine, Bundoora, VIC, Australia.
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