Abstract
Cancer immunotherapy holds great promise for the treatment of solid tumors, but its effectiveness is hindered by the recruitment of regulatory T cells (Tregs), which inhibit anti-tumor immune responses. We report here that cytosolic dsDNA, a characteristic of many cancer cells, upregulates expression of the Treg-recruitment chemokine CCL22 in multiple types of malignant epithelial cells. We also identified that interferon regulatory factor 3 (IRF3) is a key regulator of CCL22 in response to dsDNA. Both IRF3 and NF-κB are activated downstream of the stimulator of interferon genes (STING), a primary effector protein responding to multiple cytosolic dsDNA sensors. IRF3 activation by STING triggers robust expression of type I interferons, which can boost anti-tumor immune responses. Thus, STING agonists have been used clinically to activate IRF3 during immunotherapy. However, STING activation in some cases is reported to paradoxically foster a pro-tumor, immunosuppressive environment. Our finding that IRF3 regulates CCL22 in response to dsDNA suggests a possible mechanism contributing to STING-mediated immunosuppression. In addition, we found that cultured cancer cells appear able to evolve mechanisms to co-opt nucleic acid sensing pathways to upregulate CCL22, suggesting that these pathways may contribute to acquired immune evasion in tumors with increased cytosolic dsDNA.
Competing Interest Statement
The authors have declared no competing interest.
Abbreviations
- ATCC
- American Type Culture Collection
- CDN
- cyclic dinucleotide
- cGAS
- Cyclic GMP-AMP synthase
- dsDNA
- Double-stranded DNA
- GFP
- Green fluorescent protein
- IFN-γ
- Interferon gamma
- IKKε
- I-kappa-B kinase (IKK) epsilon
- IRF3
- Interferon regulatory factor 3
- MDC
- Macrophage derived chemokine
- NF-κB
- Nuclear factor kappa-light-chain-enhancer of activated B cells
- PMA
- Phorbol 12-myristate 13-acetate
- shRNA
- Short hairpin RNA
- STING
- Stimulator of interferon genes
- TBK1
- TANK-binding kinase 1
- TLR
- Toll-like receptor
- TME
- Tumor microenvironment
- TNFα
- Tumor necrosis factor alpha
- Treg
- Regulatory T cell