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Cancer systems immunology reveals myeloid—T cell interactions and B cell activation mediate response to checkpoint inhibition in metastatic breast cancer

ABSTRACT: Sensitization of the immune-suppressed tumor microenvironment (TME) of breast cancer by histone deacetylase inhibition shows promise, but the mechanisms of sensitization are unknown. We investigated the TME of breast-to-lung metastases by combining experimental and clinical data with theory. Knowledge-guided subclustering of single-cell RNA-sequencing data and cell circuits analysis identified 39 cell states and salient interactions, of which myeloid, T cell and B cell subpopulations were most affected by treatment. Using functional immunologic assays, we verified that inhibition of the ICAM pathway partially recapitulated treatment effects. Mathematical modeling of tumor-immune dynamics confirmed that tumor reduction required simultaneous modulation of multiple TME interactions. We found evidence that treatment affected anti-tumor antibody production. Analysis of patient biopsies via spatial proteomics corroborated preclinical findings: in responders we observed increased B cell activation, mature tertiary lymphoid structures, and increased CD8+ T cell—macrophage distances with treatment. Overall, this study provides a framework for the discovery of cell-cell interactions that govern responses in complex TMEs.

ORGANISM(S): Mus musculus

PROVIDER: GSE303155 | GEO | 2025/08/01

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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Cancer systems immunology reveals myeloid—T cell interactions and B cell activation mediate response to checkpoint inhibition in metastatic breast cancer

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