Relieving immune suppressive pathways in breast cancer to improve outcomes

Triple-negative breast cancer (TNBC) patients die at a disproportionately high rate due to multiple factors contributing to the aggressive and metastatic nature of the disease, exacerbated by the fact that treatment options are lacking once chemotherapy (CTX) and/or radiation therapy fails. While treatment of metastatic cancers with immune checkpoint inhibitors (ICIs) is offering great promise for many, early results from clinical trials evaluating ICIs in TNBC showed promise for only a small percentage of patients. Preclinical data indicate that myeloid cells, notably infiltrating tumor-associated macrophages (TAMs) and monocyte subtypes limit CD8+ T cell infiltration, activation and cytotoxic activity in tumor microenvironments, and thereby foster development of immunologically “cold” tumors. We hypothesized that response to ICI therapy in immunologically “cold” TNBCs would be enhanced by treating mammary tumor-bearing transgenic mice with a microtubule poison like paclitaxel (PTX) that enhances tumor immunogenicity, with macrophage-depleting/reprograming therapies, e.g., antagonists of colony-stimulating factor 1 or its receptor (CSF1/CSF1R), in combination with agents that inhibit checkpoint molecules expressed on CD8+ T cells, e.g., PD-1. Immune-competent mammary tumor-bearing MMTV-PyMT transgenic mice were randomized at day 80, and enrolled into experimental groups evaluating effects of PTX, CSF1/CSF1R antagonists, aPD-1 mAb each as monotherapy, each in combination with one other of the drugs, versus the triple combination. Where MMTV-PyMT mammary tumors are resistant to PTX, CSF1/CSF1R inhibitors and aPD-1 mAb as monotherapies, responsive tumors emerge when PTX is combined with either CSF1/CSF1R antagonists or aPD-1 mAb with primary tumor growth kinetics significantly slowed, but still growing. In contrast, mammary tumors in mice treated with the three agents together (PTX, CSF1/CSF1R antagonist, aPD-1 mAb) undergo rapid tumor regression in 60% of mice, coincident with significant diminution in presence of pulmonary metastasis as compared to PTX - CSF1/CSF1R antagonist dual combination therapy. Regressing tumors are associated with increased presence of effector memory and resident memory CD8+ T cells exhibiting antigen-specific clonal expansion (based on T-cell receptor sequence analysis). To be presented will be results from studies evaluating transcriptional programs differentially regulated in macrophages, dendritic cells, monocytes and CD8+ T cells in response to therapy and mechanistic findings underlying improved CD8+ T-cell cytotoxicity. The authors acknowledge generous support from the NIH / NCI, the Department of Defense Breast Cancer Research Program Era of Hope Scholar Expansion Award, Susan G. Komen Foundation, the Breast Cancer Research Foundation, and the Brenden-Colson Center for Pancreatic Health. Citation Format: Amanda Poissonnier, Dhaarini Murugan, Wesley Horton, Tiziana Cotechini, Hope S. Rugo, Lisa M. Coussens. Relieving immune suppressive pathways in breast cancer to improve outcomes [abstract]. In: Proceedings of the AACR Special Conference on Tumor Immunology and Immunotherapy; 2018 Nov 27-30; Miami Beach, FL. Philadelphia (PA): AACR; Cancer Immunol Res 2020;8(4 Suppl):Abstract nr A03.