The CX3CL1-CX3CR1 chemokine axis can contribute to tumor immune evasion and blockade with a novel CX3CR1 monoclonal antibody enhances response to anti-PD-1 immunotherapy

Frontiers in Immunology

Immunology

Yunfei Wang¹  Patrick Hwu¹  Xia Bu²  Ping Hua²  Michael Gomez²  James A. Torchia²  Gordon J. Freeman²  Apoorvi Chaudhri³  Ulrich von Andrian⁴  Gregory A. Lizee⁵  Michael A. Davies⁵  Shao-Hsi Hung⁶ 

[1] Department of Clinical Science, H. Lee Moffitt Cancer Center & Research Institute, Tampa, FL, United States;Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, United States;Department of Medicine, Harvard Medical School, Boston, MA, United States;Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, United States;Department of Melanoma Medical Oncology, Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX, United States;The University of Texas MD Anderson Cancer Center UTHealth Graduate School of Biomedical Sciences, Houston, TX, United States;Department of Medicine, Harvard Medical School, Boston, MA, United States;Department of Medicine, Harvard Medical School, Boston, MA, United States;Department of Immunology & HMS Center for Immune Imaging, Harvard Medical School, Boston, MA, United States;Ragon Institute of MGH, MIT and Harvard, Cambridge, MA, United States;Department of Melanoma Medical Oncology, Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX, United States;Department of Melanoma Medical Oncology, Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX, United States;The University of Texas MD Anderson Cancer Center UTHealth Graduate School of Biomedical Sciences, Houston, TX, United States;

关键词: CX3CR1;    CX3CL1;    PD-1;    tumor immune evasion;    cancer immunotherapy;   

DOI  :  10.3389/fimmu.2023.1237715

 received in 2023-06-09, accepted in 2023-08-28,  发布年份 2023

来源: Frontiers

【 摘 要 】

CX3CL1 secreted in the tumor microenvironment serves as a chemoattractant playing a critical role in metastasis of CX3CR1 expressing cancer cells. CX3CR1 can be expressed in both cancer and immune-inhibitory myeloid cells to facilitate their migration. We generated a novel monoclonal antibody against mouse CX3CR1 that binds to CX3CR1 and blocks the CX3CL1-CX3CR1 interaction. We next explored the immune evasion strategies implemented by the CX3CL1-CX3CR1 axis and find that it initiates a resistance program in cancer cells that results in 1) facilitation of tumor cell migration, 2) secretion of soluble mediators to generate a pro-metastatic niche, 3) secretion of soluble mediators to attract myeloid populations, and 4) generation of tumor-inflammasome. The CX3CR1 monoclonal antibody reduces migration of tumor cells and decreases secretion of immune suppressive soluble mediators by tumor cells. In combination with anti-PD-1 immunotherapy, this CX3CR1 monoclonal antibody enhances survival in an immunocompetent mouse colon carcinoma model through a decrease in tumor-promoting myeloid populations. Thus, this axis is involved in the mechanisms of resistance to anti-PD-1 immunotherapy and the combination therapy can overcome a portion of the resistance mechanisms to anti-PD-1.

【 授权许可】

Unknown   
Copyright © 2023 Chaudhri, Bu, Wang, Gomez, Torchia, Hua, Hung, Davies, Lizee, Andrian, Hwu and Freeman