Therapeutic KRAS^G12C inhibition drives effective interferon-mediated antitumor immunity in immunogenic lung cancers

Area of Science:

• Oncology
• Immunology
• Molecular Biology

Background:

• KRAS^G12C mutations drive lung cancer and create an immunosuppressive tumor microenvironment.
• KRAS^G12C inhibitors show promise but drug resistance is common.
• Oncogenic KRAS signaling impacts antitumor immunity, suggesting combination therapy with immune checkpoint blockade.

Purpose of the Study:

• To investigate how KRAS^G12C inhibition affects antitumor immunity in preclinical lung cancer models.
• To determine the efficacy of combining KRAS^G12C inhibitors with immune checkpoint blockade in tumors with varying immunogenicity.

Main Methods:

• Preclinical lung cancer models with diverse immunogenicity.
• Pharmacological inhibition of KRAS^G12C.
• Assessment of immune cell infiltration, activation, and antigen presentation.
• Combination therapy with immune checkpoint inhibitors (e.g., anti-PD1).

Main Results:

• KRAS^G12C inhibition reverses oncogenic KRAS-driven immunosuppression via Myc inhibition and interferon signaling.
• This leads to reduced immunosuppressive cells, increased cytotoxic T cell infiltration and activation, and enhanced antigen presentation.
• Combination therapy synergizes only in highly immunogenic tumors; KRAS^G12C inhibition does not sensitize 'cold' tumors to immunotherapy.

Conclusions:

• KRAS^G12C inhibition modulates the tumor immune microenvironment, but its combination with immune checkpoint blockade has limited efficacy in non-immunogenic lung cancers.
• These findings have critical implications for designing clinical trials combining KRAS^G12C inhibitors with anti-PD1 therapies, suggesting patient selection based on tumor immunogenicity is crucial.