Author ORCID Identifier
0000-0002-8785-234X
Date of Graduation
5-2023
Document Type
Dissertation (PhD)
Program Affiliation
Immunology
Degree Name
Doctor of Philosophy (PhD)
Advisor/Committee Chair
Dr. Gregory Lizee
Committee Member
Dr. Patrick Hwu
Committee Member
Dr. Gordon Freeman
Committee Member
Dr. Sharon Dent
Committee Member
Dr. Michael Davies
Committee Member
Dr. Kunal Rai
Abstract
CX3CL1 secreted in the tumor microenvironment serves as a chemoattractant playing a critical role in metastasis of CX3CR1 expressing cancer cells. While CX3CR1 can be expressed in both cancer and immune-inhibitory myeloid cells to facilitate their migration, the mechanisms employed by this axis on these cells to mediate immune suppression remain poorly understood. Here, we explore the immune evasion strategies implemented by this 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 mediators to attract myeloid populations, and 4) generation of tumor-inflammasome. This axis is involved in the underlying mechanisms of resistance to anti-PD-1 immunotherapy. We used a novel monoclonal antibody against mouse CX3CR1 that binds to CX3CR1, blocks the CX3CL1-CX3CR1 interaction and antagonizes the pro-tumorigenic outcome of this axis. This monoclonal antibody reduces migration of tumor cells and decreases secretion of immune suppressive soluble mediators from the tumor. 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-associated myeloid populations and their conversion into an anti-tumor phenotype.
Keywords
CX3CR1, CX3CL1, PD-1, tumor immune evasion, cancer immunotherapy