Tumor cell dissemination is facilitated through regulatory T cell-driven extracellular matrix remodeling

Regulatory T (Treg) cells function to enforce peripheral tolerance and are potent suppressors of tumor immunity. In breast cancer, we have shown that Treg cells promote tumor growth by favoring alternative activation of macrophages via suppression of IFN-γ. The tumor-associated extracellular matrix (ECM) is a key regulator of metastatic dissemination and is emerging as a critical regulator of tumor immunity. However, the reciprocal effects of the immune system on the ECM remain elusive. Using a combination of murine in vivo , ex vivo and bioengineering models we describe Treg cell-dependent changes in the tumor ECM that facilitate tumor cell migration and metastatic dissemination. Importantly, Treg cell-dependent matrisome signatures correlate with delayed survival advantage in human breast cancer samples, and are upregulated in tumor-associated macrophages (TAMs). Further, both IFN-γ and IFN-γ-sensitivity in TAMs contribute to structural and functional changes of the ECM. This work underscores a previously unrecognized role of Treg cells on the ECM that facilitates metastasis and is consistent with tissue Treg cell emergent function as critical regulators of tissue repair and cancer.