Posted May 19, 2021

Erik Wennerberg, Ph.D., Cornell University, Weill Medical College

For approximately 80% of patients diagnosed with triple-negative breast cancer (TNBC), immune checkpoint inhibitors (ICIs) have shown little to no clinical efficacy. The limited or lack of efficacy for ICIs in patients with TNBC is due to the immunosuppressive microenvironment surrounding the primary tumor, characterized by little to no infiltration of antitumor T cells or their activators, dendritic cells (DCs). Clinical studies have shown that radiation therapy in combination with ICIs is capable of eliciting an antitumor T cell response in a limited number of patients, suggesting that there are additional immunosuppressive pathways that must be overcome in order for patients to fully benefit from ICIs. Recent data has shown that CD73 is highly expressed in breast cancer and is responsible for the generation of adenosine, a highly immunosuppressive molecule that inhibits DC activation, and thus downstream activation of antitumor T cells. With a fiscal year 2016 Breast Cancer Research Program Breakthrough Fellowship Award, Dr. Wennerberg aimed to determine whether inhibiting adenosine production through blocking CD73 in combination with radiation therapy could enhance antitumor immunity in breast cancer.

In a recent Cancer Immunology Research publication, Dr. Wennerberg demonstrated the essential function of CD73 in regulating TNBC response to radiation and ICI combination therapy. Using two TNBC cell models, Dr. Wennerberg and his team showed that CD73 levels significantly increased after exposure to radiation treatment. In a mouse model of TNBC, treatment with an anti-CD73 antibody in combination with radiation therapy enhanced tumor response, extended overall survival, and resulted in complete tumor regression in a subset of mice. In addition, examination of the immune cells infiltrating the tumors of treated animals revealed an influx of activated DCs and activated antitumor T cells that co-localized within the tumor microenvironment. To determine whether CD73 blockade in combination with radiation therapy would impact distant metastatic disease, Dr. Wennerberg used a TNBC model that spontaneously metastasizes to the lung. The researchers found that radiation therapy of the primary tumor with CD73 blockade alone resulted in delayed growth of the primary tumor, but had no effect on the number of lung metastases. However, the addition of ICI’s to CD73 blockade and primary tumor irradiation led to a regression of the primary tumor and a significant decrease in the number of non-irradiated lung metastases, suggesting a systemic anti-tumor response. 

Dr. Wennerberg‘s research showed for the first time that inhibition of CD73 is a key step in reversing the immunosuppressive microenvironment that arises in irradiated TNBC tumors. In conjunction with radiation therapy and an ICI, CD73 blockade was able to offer systemic immunity against metastatic lung lesions in a mouse model of TNBC. Results from Dr. Wennerberg’s work support further preclinical and future clinical applications for the use of CD73 inhibitors in combination with radiation therapy and ICIs for the treatment of patients with TNBC, particularly metastatic TNBC. 

Publication:

Wennerberg E, Spada S, Rudqvist N-P, et al. 2020. CD73 blockade promotes dendritic cell infiltration of irradiated tumors and tumor rejection. Cancer Immunol Res 8(4):465-478.

Link:

Public and Technical Abstracts: Adenosine Blockade with Radiotherapy to Enhance Responses of Breast Cancer to Immune Checkpoint Inhibitors

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