Inhibition of RON kinase potentiates anti-CTLA-4 immunotherapy to shrink breast tumors and prevent metastatic outgrowth

Abstract

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 urgent need for improvement. We previously showed that RON, a receptor tyrosine kinase expressed in 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 in macrophages, 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, resulting in complete tumor eradication in 46% of the animals. Positive responses to therapy were associated with higher levels of T-cell activation markers and tumor-infiltrating lymphocytes. Importantly, co-inhibition of RON and anti-CTLA-4 was also effective in clearing metastatic breast cancer cells in lungs, resulting in clinical 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.

The MSP-RON axis stimulates cancer cell growth in models of triple negative breast cancer

“…In this study, we found that MSP signaling via its receptor, RON, is critical for growth and proliferation of KB1P mammary cancer cells both in vitro and in vivo. These data accord well with previous publications in other mammary tumor models that rely on artificial, ectopic expression of MSP or the RON receptor (6,7,(9)(10)(11)(12)14). Most mechanistic work on the MSP-RON axis has used cell lines derived from the MMTV-PyMT model (6,9,12,14) that overexpress MSP, or genetically engineered mouse models in which Mst1r expression is driven by the MMTV promoter (7,11).…”

“…MSP and RON (over)-expression in breast cancer specimens correlates with poor prognosis and distant recurrence (5,6), suggesting that the MSP-RON axis contributes to disease progression. Indeed, experimental models, in which MSP or RON are overexpressed or the RON receptor is inhibited or genetically deleted, show that the MSP-RON axis drives mammary tumor progression and metastasis (6)(7)(8)(9)(10)(11)(12)(13)(14).…”

Receptor tyrosine kinase, RON, promotes tumor progression by regulating EMT and the MAPK signaling pathway in human oral squamous cell carcinoma

“…In addition, Ruiz-Torres et al (48) demonstrated that the RON signaling pathway is associated with the immunosuppressive microenvironment in breast cancer. Ekiz et al (49) described that inhibition of RON kinase potentiates checkpoint immunotherapy in breast cancer. It is expected that the effectiveness of RON targeting anticancer therapy can be…”

Association of The Cytotoxic T Lymphocyte Antigen-4 +49G/A Gene Polymorphism with Susceptibility to Malignant Bone Tumors

“…CTLA-4 refers to an inhibitory molecule, which is expressed on the activated T cells, besides critically contributing to the balance existing between the pro-and anti-immune responses by downregulating the T cell signaling 23 . It has been reported that CTLA-4 overexpressed had a correlation with the poor prognosis in autoimmune diseases as well as the speci c kinds of cancer, including osteosarcoma and Ewing's sarcoma [24][25][26][27] ; however, the latent part played by CTLA-4 polymorphism in malignant bone tumors patients continue to be unclear. There are a number of research works that have investigated the correlation existing between the + 49G/A of the CTLA-4 gene and the susceptibility to malignant bone tumors, nevertheless, these results from published articles remained not just controversial but inconclusive as well.…”