RON kinase blockade in combination with anti-CTLA-4 immunotherapy shrinks breast tumors and prevents metastatic progression
Huseyin Atakan Ekiz†,1, Shu-Chin Alicia Lai†,1, Harika Gundlapalli1, Fadi Haroun1, Matthew A. Williams2, and Alana L. Welm1* 1Department of Oncological Sciences,Huntsman Cancer Institute, University of Utah, 2000 Circle of Hope, Salt Lake City, UT 84112 USA; 2Department of Pathology, Huntsman Cancer Institute, University of Utah, 2000 Circle of Hope, Salt Lake City, UT 84112 USA *Presenting author †Denotes equal contribution
The advent of immune checkpoint blockade as a new strategy for immunotherapy has changed the outlook for many aggressive cancers. Although complete tumor eradication is attainable in some cases, durable clinical responses are observed only in a small fraction of patients, underlining the critical need for improvement. Several approaches have been proposed to potentiate immunotherapies, both in clinical trials and in preclinical models. We have demonstrated that RON, a receptor tyrosine kinase expressed in resident macrophages, suppresses antitumor immune responses, and facilitates progression and metastasis of breast cancer. Here, we investigated the molecular changes that occur downstream of RON activation and whether inhibition of RON can cooperate with checkpoint immunotherapy to eradicate tumors. Activation of RON by its ligand, MSP, altered the gene expression profile of macrophages drastically and upregulated surface levels of CD80 and PD-L1, ligands for T-cell checkpoint receptors CTLA-4 and PD-1. Genetic deletion or pharmacological inhibition of RON in combination with anti-CTLA-4, but not with anti-PD-1, resulted in improved clinical responses against orthotopically transplanted tumors compared to single-agent treatment groups, and resulted in complete tumor eradication in 46% of the animals. Positive responses to therapy were associated with increased T-cell activation and better infiltrating into tumors. Importantly, co-inhibition of RON and anti-CTLA-4 was also effective in clearing metastatic breast cancer cells in the lungs and resulted in significant responses in nearly 60% of the mice. These findings suggest that RON inhibition can be a novel approach to potentiate responses to checkpoint immunotherapy in breast cancer.
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