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STING-induced regulatory B cells compromise NK function in cancer immunity
Sirui Li1,2,3, Bhalchandra Mirlekar1,2, Brandon M Johnson1,3
1Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
Nature
|October 5, 2022
Summary
Stimulator of interferon genes (STING) agonists can expand regulatory B cells, hindering anti-tumour immunity. Targeting this STING-IL-35 pathway in B cells may improve cancer therapy by enhancing natural killer cell responses.
Area of Science:
- Immunology
- Oncology
- Cancer Biology
Background:
- The tumor microenvironment often suppresses immune responses, limiting cancer treatment efficacy.
- Stimulator of Interferon Genes (STING) agonists activate innate immunity but face resistance in cancer therapies.
- Mechanisms underlying resistance to STING agonists in solid tumors remain unclear.
Purpose of the Study:
- To investigate the impact of STING agonists on the tumor microenvironment in pancreatic cancer.
- To elucidate the mechanisms by which STING agonists affect immune cells within tumors.
- To identify novel therapeutic strategies to overcome resistance to STING-based cancer therapies.
Main Methods:
- Administration of various STING agonists (including cGAMP) to human and mouse pancreatic cancer models.
- Analysis of B cell populations, specifically interleukin-35 (IL-35) expressing regulatory B cells.
- Assessment of STING signaling pathways (IRF3, type I interferon) in B cells.
- Evaluation of tumor control following STING pathway modulation in B cells.
- Investigation of the effects of IL-35 blockade or genetic ablation on tumor growth.
- Assessment of natural killer (NK) cell proliferation and anti-tumor activity.
Main Results:
- STING agonists, including cGAMP, induce expansion of IL-35+ regulatory B cells in pancreatic cancer.
- cGAMP-induced IL-35 expression in B cells is dependent on IRF3 but independent of type I interferon.
- Loss of STING signaling in B cells enhances tumor control in preclinical models.
- Blocking or ablating IL-35 in B cells reduces tumor growth.
- The STING-IL-35 axis in B cells suppresses natural killer (NK) cell proliferation and anti-tumor responses.
Conclusions:
- STING agonists can paradoxically promote immunosuppression by expanding regulatory B cells via the IL-35 pathway.
- This STING-IL-35 axis in B cells represents an intrinsic barrier to STING agonist monotherapy.
- Targeting the STING-IL-35 pathway in B cells, potentially combined with IL-35 blockade, offers a strategy to enhance NK cell-mediated anti-tumor immunity and overcome treatment resistance.
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