Cancer cell-derived type I interferons instruct tumor monocyte polarization

Area of Science:

• Immunology
• Cancer Biology
• Molecular Oncology

Background:

• Monocytes are crucial immune cells that regulate antitumor immunity and immunotherapy efficacy.
• Understanding factors controlling monocyte function within the tumor microenvironment is essential for advancing cancer immunotherapies.

Purpose of the Study:

• To investigate the role of endogenous cancer cell-derived type I interferons (IFNs) in regulating tumor monocyte polarization.
• To identify distinct monocyte subsets and their association with immunotherapy response.

Main Methods:

• Single-cell transcriptomic profiling of human and mouse tumors.
• Development of a strategy to distinguish immunostimulatory and immunosuppressive monocytes using CD88 and Sca-1 surface markers.
• Analysis of cGAS-STING pathway activation and type I IFN production in cancer cells.

Main Results:

• Cancer cell-derived type I IFNs were identified as key regulators of monocyte functional polarization.
• A method was developed to separate immunostimulatory (CD88+ Sca-1-) from immunosuppressive (CD88- Sca-1+) tumor monocytes.
• Activation of the cGAS-STING pathway in cancer cells led to the polarization of immunostimulatory monocytes, correlating with anti-PD-1 immunotherapy response in mice.
• Human cancer cells produce type I IFNs that polarize monocytes, and an immunostimulatory monocyte signature predicts response to anti-PD-1 therapy in patients.

Conclusions:

• Endogenous type I IFNs produced by cancer cells play a critical role in shaping the tumor immune microenvironment by polarizing monocytes.
• Distinct monocyte subsets can be identified and their functional states modulated by cancer cell-intrinsic signaling pathways.
• These findings highlight cancer cell-derived IFNs as potential targets for enhancing immunotherapy efficacy.