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Background Combination treatment with immunotherapy (i.e., anti-PD-1 or anti-PD-L1 antibodies) plus concurrent chemotherapy (cisplatin or carboplatin) is now part of the standard of care for non-small cell lung cancer (NSCLC) patients. Our study identifies a previously unknown and paradoxical chemotherapy-induced immune suppressive pathway. We show that cisplatin induces prostaglandin E2 (PGE 2) production in tumor cells, which upregulates the ectoenzyme CD73 on monocytic myeloid-derived suppressor cells (M-MDSCs). CD73-expressing M-MDSCs produce extracellular adenosine, a potent immunosuppressive metabolite that inhibits effector T-cell activation within the tumor microenvironment (TME). To counteract this immunosuppressive pathway, we evaluated [PEGylated]-Adenosine Deaminase (PEG-ADA), an FDA-approved agent that depletes extracellular adenosine.Methods Human M-MDSCs were generated by co-culturing CD14 + monocytes isolated from healthy donor’s PBMCs with A375 melanoma or A549 NSCLC cells. For T cell suppression assays, M-MDSCs from human NSCLC were cultured with autologous T cells stimulated with anti-CD3 and anti-CD28 antibodies. For PEG-ADA efficacy studies, KP1.9 NSCLC-bearing mice were treated with PEG-ADA (2 Units/mouse) with or without anti-PD-1 antibody (250 µg/mouse). Mass spectrometry was used to analyze fatty acids and PGE2 levels in cisplatin-treated tumors. Protein expression were determined by Western blot. Cytokines in tumor cell supernatants were analyzed by ELISA. GraphPad Prism 8.0 software was used for statistical analyses (Student’s t-test or ANOVA).Results Our data show that cisplatin significantly enhances steady state lung cancer cell-secreted PGE 2, which in turn upregulates the expression of the CD73 enzyme on M-MDSCs. Furthermore, our data show that CD73+ M-MDSCs generate adenosine, which suppresses effector T cell activation within the TME, thereby impairing the effectiveness of chemo-immunotherapy. Our results indicate that chemotherapy activates fatty acid synthase (FAS) which then leads to accumulation of polyunsaturated fatty acids, such as arachidonic acid. Accumulation of fatty acids activates NF-kB which then activates the CREB transcription factor, resulting in an increase in COX-2 and, subsequently, increased production of PGE2. To reduce intratumoral adenosine levels, we investigated the use of PEG-ADA, an FDA-approved drug. Our findings demonstrate that depleting adenosine with PEG-ADA enhances anti-tumor immunity and sensitizes NSCLC to immunotherapy.Conclusions Our study uncovers a previously unrecognized immunosuppressive mechanism driven by cisplatin-induced PGE 2-mediated induction of CD73 enzyme on M-MDSCs and subsequent adenosine production (figure 1). Our studies establish that adding PEG-ADA (a drug that is FDA-approved for a non-cancer indication) to standard chemo-immunotherapy as a promising strategy that can be quickly translated into improved NSCLC treatment regimens.Abstract 708 Figure 1Graphical abstract. Targeting adenosine metabolism and modulation of CD73+ M-MDSC increases chemoimmunotherapeutic efficacy in NSCLC