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Tumors with active microenvironmental type-I interferon response are sensitive to inhibitors of heme degradation

ABSTRACT: The tumor microenvironment (TME) is highly heterogeneous and plays a critical role in determining the success of therapeutic interventions. Identifying TMEs that are susceptible to specific therapies enables the development of more personalized and effective treatments. In this study, using a spontaneous murine model of breast cancer, we characterize a TME that is sensitive to inhibitors of the heme degradation pathway mediated by heme oxygenase (HO) activity, leading to CD8+ T- and NK-cell-dependent tumor control. A key feature of this TME is a chronic type-I interferon (IFN) signal, which is crucial in orchestrating an anti-tumor immune response. Notably, similar TMEs are found in human breast cancer and are associated with patient prognosis. Leveraging these insights, we demonstrate that combining a STING agonist, which induces type-I IFN responses, with an HO inhibitor results in a synergistic effect, enhancing tumor control. This study identifies HO activity as a potential resistance mechanism to type-I IFN responses, providing a novel strategy for overcoming immune evasion in cancer therapy. As part of this investigation, multiplex gene expression analysis was performed on 770 genes, including 40 housekeeping genes, from RNA extracted from MMTV-PyMT tumors. The samples were processed using the nCounter® platform, with RNA isolated, quantified, and assessed for integrity following standardized protocols, allowing for detailed molecular characterization of the TME.

ORGANISM(S): Mus musculus

PROVIDER: GSE279433 | GEO | 2025/06/19

REPOSITORIES: GEO

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Project description:Murine syngeneic tumor models have been extensively used for cancer research for several decades. These tumor models are very simplistic cancer models, but recent reports have, however, indicated that the different inoculated cancer cells can lead to the formation of very different tumor microenvironments (TMEs). Importantly, these types of tumor models have been instrumental in driving the discovery and development of cancer immunotherapies. In order to gain more knowledge from studies based on syngeneic tumor models it is essential to know in more details the cellular and molecular composition of the TME in the different models. It is also important to know about other parameters such as the mechanical tumor stiffness of the different models. This type of knowledge can be used for the rational selection of tumor models for specific studies and for studying the correlation between different tumor-promoting parameters. Here, we compare the tumor microenvironment (TME) of tumors derived from six different commonly used syngeneic tumor models. Using flow cytometry and transcriptomic analyses we show that strikingly different TMEs are formed by the different cancer cell lines. The differences are reflected as changes in abundance and phenotype of myeloid, lymphoid and stromal cells in the tumors. The gene expression profile of tumors from the different models supported the different cellular composition of the TMEs and indicate that different mechanisms of immune suppression are employed in the different tumor models. Cancer-associated fibroblasts also acquire very different phenotypes in the different tumor models. These differences include differential expression of genes encoding ECM proteins, MMPs, and immunosuppressive factors. In consistence with these observations, the mechanical stiffness of the tumors from different models do not simply correlate to the number of infiltrating CAFs even though collagen produced by stromal cells is an important reason for the increased stiffness of tumors. The gene expression profiles suggest that CAFs can contribute to the formation of an immunosuppressive TME and flow cytometry analyses show CAFs express high levels of PD-L1 in the immunogenic tumor models MC38 and CT26. Comparison with CAF subsets identified in other studies show that CAFs from the different models are skewed towards specific subsets. CAFs from CT26 tumors show similarities to iCAFs and myCAFs, and in athymic mice without infiltrating cytotoxic T cells, CAFs express lower levels of PD-L1 and lower levels of fibroblast activation markers.

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Tumors with active microenvironmental type-I interferon response are sensitive to inhibitors of heme degradation

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