Enzymatic depletion of adenosine to overcome resistance to immune checkpoint inhibitors in non-small cell lung cancer

Abstract Despite the remarkable outcome of immune checkpoint inhibitors (ICIs) in non-small cell lung cancer (NSCLC), a large number of patients remain unresponsive to this therapy. A key factor of the unresponsiveness to ICIs is intrinsic therapeutic resistance where monocytic myeloid-derived suppressor cells (M-MDSCs) contribute significantly via suppressing CD8 +T cell mediated anti-tumor response. Our results showed that in tumor microenvironment (TME), tumor cells derived PGE 2; a prostaglandin that directly induces CD73 (an ecto-nucleotidase that converts AMP to immunosuppressive adenosine) expression in M-MDSCs; consequently, CD73 expressing M-MDSCs suppress T cells via adenosine thus confer resistance to ICIs. In addition, we have shown that the depletion of adenosine via PEGylated Adenosine Deaminase (PEG-ADA) can reinvigorate CD8 +T cells, ultimately enhance the anti-tumor immunity.