p38MAPKa stromal reprogramming sensitizes metastatic breast cancer to immunotherapy.

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.