| Autor: |
Omar S. Sarkar, Howard Donninger, Numan Al Rayyan, Lewis C. Chew, Bryce Stamp, Xiang Zhang, Aaron Whitt, Chi Li, Melissa Hall, Robert A. Mitchell, Alfred Zippelius, John Eaton, Jason A. Chesney, Kavitha Yaddanapudi |
| Rok vydání: |
2022 |
| Popis: |
Although immune checkpoint inhibitor (ICI) therapy has provided robust results in many cancer types such as melanoma and lung cancer, a large percentage of patients remain unresponsive to this therapy. Emerging evidence strongly suggests that one of the contributing factors in ICI resistance is monocytic myeloid derived suppressor cells (M-MDSCs) that accumulate in late-stage cancer patients. These M-MDSCs are a subset of innate immune cells and possess potent immunosuppressive activity against T lymphocytes. Here we provide evidence of a mechanism by which CD73-expressing M-MDSCs in the tumor microenvironment (TME) exhibit superior T cell suppressor function via adenosine. We show that tumor-derived PGE2, a prostaglandin frequently found at high levels in the TME, directly induces CD73 expression in M-MDSCs by initiating a signaling pathway that is mediated by both Stat3 and CREB. The resulting CD73 overexpression induces elevated levels of adenosine, a nucleoside with strong T cell suppressive activity, culminating in the suppression of CD8+ T cell-mediated anti-tumor responses. We also show that depletion of adenosine in the TME by the repurposed drug PEGylated Adenosine Deaminase (PEG-ADA) increases CD8+ T cell anti-tumor activity and enhances response to ICI therapy in preclinical models of cancer. Our results suggest that use of PEG-ADA is a viable therapeutic option to overcome ICI therapeutic resistance in advanced cancer patients. |
| Databáze: |
OpenAIRE |
| Externí odkaz: |
|
