Fatty acids in the tumor microenvironment reprogram neutrophils to induce immunosuppression via adenosine.
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 PPARα 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.
EDRN PI Authors
Medline Author List
- Arya SB
- Bell HN
- Carpenter E
- Dalal PJ
- Gonzalez FJ
- Green MD
- Huang W
- Huber A
- Jasewicz H
- Kasano-Camones CI
- Kotla NK
- Kumar R
- Lee ZH
- Lyssiotis CA
- Mallappa AV
- Moon JJ
- Parent CA
- Patterson AD
- Rebernick R
- Sajjakulnukit P
- Shah YM
- Singhal R
- Solanki S
- Stoffel EM
- Takahashi S
- Zhang NW
- Zou W
- di Magliano MP