Posted May 26, 2015
Dr. Lisa Coussens, Oregon Health & Science University
While standard treatment methods have improved the overall outlook and quality of life for women with breast cancer, too many women still succumb to the disease. Furthermore, 20%-30% of women diagnosed with a favorable prognosis still develop metastatic disease within 10 years. More thorough and accurate prognostic assays that accurately predict risk of disease metastasis or recurrence are needed, as are treatments that suppress tumor growth. Dr. Lisa Coussens, recipient of a Breast Cancer Research Program Era of Hope Scholar Award, and Scholar Expansion Award, has discovered that the research area of tumor-specific inflammation may yield answers to both of these needs. Although breast cancer has not been linked definitively to underlying inflammation or infection, it does display tumor-associated inflammation marked by infiltration of developing tumors by immune cells, the most abundant myeloid cell being macrophages, known to provide growth and survival factors that aid in metastasis. This information warrants investigation into novel treatments that target the tumor-specific immune response, which may be particularly useful for late-stage breast cancer patients.
Previously, Dr. Coussens was able to show that the pulmonary metastasis of mouse mammary tumors is functionally regulated by two types of immune cells: CD4+ T cells and macrophages. Her study determined that blocking macrophage infiltration into the tumors enhanced efficacy of standard-of-care chemotherapy (CTX). This finding correlated highly with data from human breast cancer patients showing that recurrence-free survival could be stratified based upon macrophage and T cell infiltration. Moreover, when macrophage infiltration into mammary tumors was blocked, chemosensitivity to paclitaxel was increased, resulting in reduced primary tumor growth, 85% reduction in metastases, and increased survival. In translating these basic science discoveries to the clinic, Dr. Coussens partnered with clinical colleagues Dr. Hope Rugo (UCSF) and E. Shelley Hwang (Duke Univ) to propose therapeutic targeting of macrophages in women with triple negative breast cancer. As such, the three collaborators were awarded a Komen Promise grant that is supporting an investigator-initiated clinical trial evaluating efficacy of this approach (NCT01596751).
An FY10 Era of Hope Scholar Expansion Award allowed Dr. Coussens to initiate an integrated, multidisciplinary project to evaluate the clinical benefit of macrophage modulation in preclinical mouse models of breast cancer, with the goals of facilitating biomarker identification and informing clinical trials of CTX in combination with known macrophage-antagonists. The hypothesis is that components of the macrophage response in breast cancer can be identified to serve as biomarkers for risk stratification and that these components can be effectively targeted for therapeutic intervention. The prediction is that the intervention will result in decreased late-stage breast cancer development and metastasis when combined with CTX. In a recent article in Cancer Immunology Research*, Dr. Coussens wrote that clinical responses to radiotherapy can also be improved by neutralizing the TH2-based programs that drive tumorigenic and immune-suppressive pathways in mammary tumors. Furthermore, Dr. Coussens expects that these novel strategies will be able to better harness the power of dendritic cell-based vaccines that may induce durable tumor repression. This highly translational project will allow for an entirely new treatment strategy for breast cancer where a novel immune-based approach will be leveraged to potentiate the effect of cytotoxic chemotherapy in patients with breast cancer.
*Shiao SL, Ruffell B, DeNardo D et al. In press. TH2-polarized CD4+ T cells and macrophages limit efficacy of radiation therapy. Cancer Immunol Res.
histology of macrophages (red) in mammary carcinomas (blue) with blood vessels (green), and areas of hypoxia (yellow)
Ruffell B and Coussens LM. 2015. Macrophages and therapeutic resistance in cancer. Cancer Cell 27(4):462-472.
Shiao SL, Ruffell B, DeNardo D, Faddegon B, Park CC, and Coussens LM. 2015. TH2-polarized CD4+ T cells and macrophages limit efficacy of radiation therapy. Cancer Immunology Research [Epub ahead of print]
Ruffell B, Chang-Strachan D, Chan V, Rosenbusch A, Ho CM, Pryer N, Daniel D, Hwang ES, Rugo HS, Coussens LM. 2014. Macrophage IL-10 blocks CD8+ T cell-dependent responses to chemotherapy by suppressing IL-12 expression in intratumoral dendritic cells. Cancer Cell 26(5):623-637.
Coussens LM, Zitvogel L, and Palucka AK. 2013. Neutralizing tumor-promoting chronic inflammation: A magic bullet? Science 339(6117):286-291.