"Therapeutic Targeting of T-cell suppressive Breast Tumor Microenvironment Vulnerabilities to Elicit Tumor Control"
- Amanda Poissonnier, Ph.D.
- Research Assistant Professor
- Coussens Laboratory | Dept. of Cell, Developmental and Cancer Biology
- Oregon Health & Science University Knight Cancer Institute
Immune checkpoint inhibitors (ICIs) have reshaped cancer therapy, yet durable responses in solid tumors remain limited by the immunosuppressive tumor microenvironment (TME). In breast cancer, T cell-suppressive myelomonocytic populations are a key driver of ICI resistance. However, the molecular circuitry governing their activity and therapeutic tractability remains incompletely defined. By integrating cellular and molecular correlates from clinical studies with findings from preclinical transgenic models of mammary adenocarcinoma, we investigated whether epigenetic reprogramming of the TME could overcome this resistance. We first established that CSF1 receptor (CSF1R) inhibition remodels the myelomonocytic compartment and synergizes with PD-1 blockade to improve tumor control beyond what either agent achieves alone. Layering epigenetic modulation onto this combinatorial backbone further dismantles T cell suppression within the TME, unlocking a multi-arm immune response that monotherapy or dual-therapy regimens fail to engage. At the mechanistic level, neoplastic-intrinsic modulations engage innate immune sensing pathways, triggering dendritic cell activation and downstream coordination of B and T cell responses. This cascade establishes immunological memory and maintains sustained selective pressure against tumor cells, suggesting that the benefit extends well beyond the treatment window. Together, these findings delineate an epigenetically controlled signaling axis that sits at the intersection of myeloid immunosuppression and ICI efficacy, and that is amenable to pharmacological intervention with clinically available agents. This work provides a mechanistic rationale for a sequential combination strategy and offers a translatable framework for improving ICI outcomes in breast cancer patients with immunosuppressive tumor microenvironments.