Fatty acids in the tumor microenvironment reprogram neutrophils to induce immunosuppression via adenosine
Singhal, R.; Zhang, N. W.; Lee, Z. H.; Bell, H. N.; Dalal, P. J.; Solanki, S.; Huang, W.; Rebernick, R.; Sajjakulnukit, P.; Jasewicz, H.; Kumar, R.; Kotla, N. K.; Huber, A.; Vijay, A.; Arya, S. B.; Takahashi, S.; Kasano-Camones, C. I.; Carpenter, E.; Pasca di Magliano, M.; Moon, J. J.; Parent, C.; Gonzalez, F. J.; Patterson, A. D.; Green, M. D.; Zou, W.; Stoffel, E. M.; Lyssiotis, C. A.; Shah, Y. M.
Show abstract
As solid tumors progress, the tumor microenvironment (TME) becomes increasingly immunosuppressive, impairing cytotoxic T-cell activity and limiting the efficacy of the immune checkpoint blockade. However, the mechanistic drivers of this immunosuppression remain poorly understood. Here, we identify a tumor-derived lipid-neutrophil-adenosine axis as a critical regulator of immune suppression in advanced colorectal cancer (CRC). We show that fatty acids enriched in tumor interstitial fluid reprogram neutrophils to generate adenosine via PPAR activation, leading to T-cell suppression. Using AB928, a dual A2aR/A2bR adenosine receptor antagonist currently in clinical trials, we restored T-cell proliferation, effector function, and tumor-killing capacity in vitro and in vivo. Importantly, AB928 synergized with anti-PD-1 therapy to enhance survival in an autochthonous model of metastatic CRC. Our findings define a metabolic immune evasion mechanism in the TME and provide a rationale for targeting neutrophil-derived adenosine signaling to improve immunotherapy responses in CRC and other solid tumors.
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