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Tyrosine Kinase Inhibitor Cabozantinib Inhibits Murine Renal Cancer by Activating Innate and Adaptive Immunity

BACKGROUND: Advanced renal cell carcinoma (RCC) has a very dismal prognosis. Cabozantinib, a tyrosine kinase inhibitor, has been approved for the treatment of advanced RCC. However, the impact of cabozantinib on the immune microenvironment of RCC remains poorly understood. METHODS: Kaplan-Meier surv...

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Autores principales: Liu, Hongyan, Sun, Shishuo, Wang, Gang, Lu, Mengmeng, Zhang, Xiaokang, Wei, Xiaohuan, Gao, Xiaoge, Huang, Chao, Li, Zhen, Zheng, Junnian, Zhang, Qing
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Frontiers Media S.A. 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8089383/
https://www.ncbi.nlm.nih.gov/pubmed/33954115
http://dx.doi.org/10.3389/fonc.2021.663517
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author Liu, Hongyan
Sun, Shishuo
Wang, Gang
Lu, Mengmeng
Zhang, Xiaokang
Wei, Xiaohuan
Gao, Xiaoge
Huang, Chao
Li, Zhen
Zheng, Junnian
Zhang, Qing
author_facet Liu, Hongyan
Sun, Shishuo
Wang, Gang
Lu, Mengmeng
Zhang, Xiaokang
Wei, Xiaohuan
Gao, Xiaoge
Huang, Chao
Li, Zhen
Zheng, Junnian
Zhang, Qing
author_sort Liu, Hongyan
collection PubMed
description BACKGROUND: Advanced renal cell carcinoma (RCC) has a very dismal prognosis. Cabozantinib, a tyrosine kinase inhibitor, has been approved for the treatment of advanced RCC. However, the impact of cabozantinib on the immune microenvironment of RCC remains poorly understood. METHODS: Kaplan-Meier survival curves were constructed to examine the correlation between intratumor infiltration of neutrophils and patient prognosis in RCC. Infiltration and effector function of neutrophils and T cells in response to cabozantinib treatment were investigated in a murine RCC model. RESULTS: A retrospective study of 307 RCC patients indicated that neutrophils were recruited into tumor tissues, and increased neutrophil infiltration was associated with improved clinical outcomes. In a murine model of RCC, cabozantinib treatment significantly increased both intratumor infiltration and anti-tumor function of neutrophils and T cells. Mechanistically, we found that cabozantinib treatment induced expression of neutrophil-related chemokines (CCL11 and CXCL12) and T cell-related chemokines (CCL8 and CX3CL1) in the tumor microenvironment. Furthermore, depletion of neutrophils and CD8(+) T cells compromised the therapeutic efficacy of cabozantinib. Importantly, cabozantinib treatment induced long-term anti-tumor T cell response. CONCLUSIONS: Our study revealed novel mechanisms of the therapeutic effects of cabozantinib on RCC by activating both neutrophil-mediated innate immunity and T cell-mediated adaptive immunity. These findings are of great significance for guiding the clinical use of cabozantinib and provide a good candidate for future combination therapy with T-cell therapies or other immunotherapies.
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spelling pubmed-80893832021-05-04 Tyrosine Kinase Inhibitor Cabozantinib Inhibits Murine Renal Cancer by Activating Innate and Adaptive Immunity Liu, Hongyan Sun, Shishuo Wang, Gang Lu, Mengmeng Zhang, Xiaokang Wei, Xiaohuan Gao, Xiaoge Huang, Chao Li, Zhen Zheng, Junnian Zhang, Qing Front Oncol Oncology BACKGROUND: Advanced renal cell carcinoma (RCC) has a very dismal prognosis. Cabozantinib, a tyrosine kinase inhibitor, has been approved for the treatment of advanced RCC. However, the impact of cabozantinib on the immune microenvironment of RCC remains poorly understood. METHODS: Kaplan-Meier survival curves were constructed to examine the correlation between intratumor infiltration of neutrophils and patient prognosis in RCC. Infiltration and effector function of neutrophils and T cells in response to cabozantinib treatment were investigated in a murine RCC model. RESULTS: A retrospective study of 307 RCC patients indicated that neutrophils were recruited into tumor tissues, and increased neutrophil infiltration was associated with improved clinical outcomes. In a murine model of RCC, cabozantinib treatment significantly increased both intratumor infiltration and anti-tumor function of neutrophils and T cells. Mechanistically, we found that cabozantinib treatment induced expression of neutrophil-related chemokines (CCL11 and CXCL12) and T cell-related chemokines (CCL8 and CX3CL1) in the tumor microenvironment. Furthermore, depletion of neutrophils and CD8(+) T cells compromised the therapeutic efficacy of cabozantinib. Importantly, cabozantinib treatment induced long-term anti-tumor T cell response. CONCLUSIONS: Our study revealed novel mechanisms of the therapeutic effects of cabozantinib on RCC by activating both neutrophil-mediated innate immunity and T cell-mediated adaptive immunity. These findings are of great significance for guiding the clinical use of cabozantinib and provide a good candidate for future combination therapy with T-cell therapies or other immunotherapies. Frontiers Media S.A. 2021-04-19 /pmc/articles/PMC8089383/ /pubmed/33954115 http://dx.doi.org/10.3389/fonc.2021.663517 Text en Copyright © 2021 Liu, Sun, Wang, Lu, Zhang, Wei, Gao, Huang, Li, Zheng and Zhang https://creativecommons.org/licenses/by/4.0/This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
spellingShingle Oncology
Liu, Hongyan
Sun, Shishuo
Wang, Gang
Lu, Mengmeng
Zhang, Xiaokang
Wei, Xiaohuan
Gao, Xiaoge
Huang, Chao
Li, Zhen
Zheng, Junnian
Zhang, Qing
Tyrosine Kinase Inhibitor Cabozantinib Inhibits Murine Renal Cancer by Activating Innate and Adaptive Immunity
title Tyrosine Kinase Inhibitor Cabozantinib Inhibits Murine Renal Cancer by Activating Innate and Adaptive Immunity
title_full Tyrosine Kinase Inhibitor Cabozantinib Inhibits Murine Renal Cancer by Activating Innate and Adaptive Immunity
title_fullStr Tyrosine Kinase Inhibitor Cabozantinib Inhibits Murine Renal Cancer by Activating Innate and Adaptive Immunity
title_full_unstemmed Tyrosine Kinase Inhibitor Cabozantinib Inhibits Murine Renal Cancer by Activating Innate and Adaptive Immunity
title_short Tyrosine Kinase Inhibitor Cabozantinib Inhibits Murine Renal Cancer by Activating Innate and Adaptive Immunity
title_sort tyrosine kinase inhibitor cabozantinib inhibits murine renal cancer by activating innate and adaptive immunity
topic Oncology
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8089383/
https://www.ncbi.nlm.nih.gov/pubmed/33954115
http://dx.doi.org/10.3389/fonc.2021.663517
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