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

Authors

Apoorvi Chaudhri
Xia Bu
Yunfei Wang
Michael Gomez
James A Torchia
Ping Hua
Shao-Hsi Hung
Michael A Davies
Gregory A Lizee
Ulrich von Andrian
Patrick Hwu
Gordon J Freeman

Publication Date

1-1-2023

Journal

Frontiers in Immunology

Abstract

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.

Keywords

Mice, Animals, Antibodies, Monoclonal, Tumor Escape, Chemokine CX3CL1

Comments

Supplementary Materials

Data Availability Statement

PMID: 37771579