Opposing Functions of Interferon Coordinate Adaptive and Innate Immune Responses to Cancer Immune Checkpoint Blockade

Area of Science:

• Immunology
• Cancer Biology
• Molecular Biology

Background:

• Interferon-gamma (IFNG) enhances immune function but also induces T cell exhaustion via PDL1.
• The integration of these opposing IFNG effects on anti-tumor immunity and immune checkpoint blockade (ICB) is not fully understood.

Purpose of the Study:

• To elucidate how IFNG signaling in cancer cells and immune cells is integrated to regulate anti-tumor immunity.
• To investigate the impact of modulating IFNG signaling on immune cell function and tumor rejection.

Main Methods:

• Analysis of interferon-stimulated genes (ISGs) in cancer and immune cells upon IFNG signaling inhibition.
• Characterization of T cell exhaustion (T_EX) and innate immune cell populations (ILC1s) in tumors.
• Evaluation of tumor rejection in models with varying antigenicity and MHC-I status.
• Correlation analysis of IFNG signaling perturbations with ICB response in melanoma and lung cancer patients.

Main Results:

• Inhibiting tumor IFNG signaling decreases ISGs in cancer cells but increases them in immune cells, driven by T_EX-produced IFNG.
• T_EX cells mediate tumor rejection in antigen-rich tumors.
• In tumors with neoantigen or MHC-I loss, T_EX-derived IFNG promotes innate immune cell maturation, including PD1⁺TRAIL⁺ ILC1s.
• Blocking tumor IFNG signaling enhances innate immune killing by disabling an inhibitory circuit involving PD1 and TRAIL.

Conclusions:

• Interferon signaling in cancer and immune cells establishes an opposing regulatory relationship that limits both adaptive and innate anti-tumor immune responses.
• Perturbing this regulatory relationship is linked to improved ICB response in melanoma and lung cancer patients, irrespective of tumor mutational burden.