Tumor microenvironments with an active type I IFN response are sensitive to inhibitors of heme degradation
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Dominika Sosnowska Tik Shing Cheung Jit Sarkar James W Opzoomer Karen T Feehan Joanne E Anstee Chloé Amelia Woodman Mohamed Reda Keddar Kalum Clayton Samira Ali William Macmorland Dorothy D Yang James Rosekilly Cheryl E Gillett Francesca Ciccarelli Richard Buus James Spicer Anita Grigoriadis James N ArnoldAbstract
The tumor microenvironment (TME) is highly heterogeneous and can dictate the success of therapeutic interventions. Identifying TMEs that are susceptible to specific therapeutic interventions paves the way for more personalized and effective treatments. In this study, using a spontaneous murine model of breast cancer, we characterize a TME that is responsive to inhibitors of the heme degradation pathway mediated by heme oxygenase (HO), resulting in CD8+ T- and NK-cell-dependent tumor control. A hallmark of this TME is a chronic type-I interferon (IFN) signal that is directly involved in orchestrating the anti-tumor immune response. Importantly, we identify that similar TMEs exist in human breast cancer which are associated with patient prognosis. Leveraging these observations, we demonstrate that combining a STING agonist, which induces type-I IFN responses, with an HO inhibitor produces a synergistic effect leading to superior tumor control. This study highlights HO activity as a potential resistance mechanism for type-I IFN responses in cancer offering a novel avenue for overcoming immune evasion in cancer therapy.
Journal details
Journal
JCI insight
Volume
10
Issue number
16
Pages
e191017
Available online
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Publisher website (DOI)
10.1172/jci.insight.191017
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Europe PubMed Central
40627458
Pubmed
40627458
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