Metastatic breast cancer is an intractable disease that responds poorly to immunotherapy. We show that p38MAPKa inhibition (p38i) limits tumor growth by reprograming the metastatic tumor microenvironment in a CD4+ T cell, IFNy, and macrophage dependent manner. To identify targets that further increased p38i efficacy, we utilized a stromal labeling approach and single cell RNA sequencing. Thus, we combined p38i and an OX40 agonist that synergistically reduced metastatic growth and increased overall survival. Intriguingly, patients with a p38i metastatic stromal signature had better overall survival that was further improved by the presence of an increased mutational load, leading us to ask if our approach would be effective in antigenic breast cancer. The combination of p38i, anti-OX40, and cytotoxic T cell engagement cured mice of metastatic disease and produced long-term immunologic memory. Our findings demonstrate that a detailed understanding of the stromal compartment can be used to design effective anti-metastatic therapies.
DNA oligonucleotides containing site-specific N7-guanine monoadducts of cisplatin, diepoxybutane, and epichlorohydrin were used as templates for DNA synthesis by two bacterial DNA polymerases and human polymerase β. These polymerases were able to bypass the lesions effectively, although the efficiency was decreased, with inhibition increasing with the size of the lesion. Fidelity of incorporation was essentially unaltered, suggesting that N7-guanine monoadducts do not significantly contribute to the mutational spectra of these agents.
<div>Abstract<p>Metastatic breast cancer is an intractable disease that responds poorly to immunotherapy. We show that p38MAPKα inhibition (p38i) limits tumor growth by reprogramming the metastatic tumor microenvironment in a CD4<sup>+</sup> T cell-, IFNγ-, and macrophage-dependent manner. To identify targets that further increased p38i efficacy, we utilized a stromal labeling approach and single-cell RNA sequencing. Thus, we combined p38i and an OX40 agonist that synergistically reduced metastatic growth and increased overall survival. Intriguingly, patients with a p38i metastatic stromal signature had better overall survival that was further improved by the presence of an increased mutational load, leading us to ask if our approach would be effective in antigenic breast cancer. The combination of p38i, anti-OX40, and cytotoxic T-cell engagement cured mice of metastatic disease and produced long-term immunologic memory. Our findings demonstrate that a detailed understanding of the stromal compartment can be used to design effective antimetastatic therapies.</p>Significance:<p>Immunotherapy is rarely effective in breast cancer. We dissected the metastatic tumor stroma, which revealed a novel therapeutic approach that targets the stromal p38MAPK pathway and creates an opportunity to unleash an immunologic response. Our work underscores the importance of understanding the tumor stromal compartment in therapeutic design.</p><p><i><a href="https://aacrjournals.org/cancerdiscovery/article/doi/10.1158/2159-8290.CD-13-6-ITI" target="_blank">This article is highlighted in the In This Issue feature, p. 1275</a></i></p></div>
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