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

Oncoimmunology
Huseyin Atakan EkizAlana L Welm

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 ...Continue Reading

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Citations

Nov 22, 2019·Acta Neuropathologica Communications·Krissie LentingWilliam P Leenders
Oct 30, 2020·Frontiers in Immunology·Lingtong HuangHangping Yao
Nov 18, 2020·Journal of Cellular Physiology·Yibing ChenZhengzhi Zou
Feb 20, 2021·Journal of Controlled Release : Official Journal of the Controlled Release Society·Lian LiJiyuan Yang

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Methods Mentioned

BETA
transgenic
RNAseq
flow cytometry
PMA
lavage
2500
physical

Software Mentioned

DESeq2
IPA
ImageJ
Fiji
Ingenuity Pathway Analysis software
FlowJo
RNAseq
Image J

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