Activation of CD8⁺ T Cells Contributes to Antitumor Effects of CDK4/6 Inhibitors plus MEK Inhibitors

Area of Science:

• Oncology
• Immunology
• Molecular Biology

Background:

• Concurrent MEK and CDK4/6 inhibition is a promising strategy for advanced-stage mutant BRAF/NRAS solid tumors.
• The impact of these combined inhibitors on the tumor immune microenvironment, particularly in melanoma, remains poorly understood.

Purpose of the Study:

• To investigate the effects of combined MEK and CDK4/6 inhibition on the tumor immune microenvironment in BRAF-mutant melanoma.
• To elucidate the immune-based mechanisms underlying treatment response and resistance.

Main Methods:

• Utilized immunocompetent and immune-deficient mouse models of BRAF-mutant melanoma.
• Administered MEK inhibitor (MEKi) and CDK4/6 inhibitor (CDK4/6i) alone and in combination.
• Assessed tumor immunogenicity, T-cell infiltration, and expression of immune molecules like CD137L.
• Investigated the role of CD8+ T cells and CD137 signaling in tumor regrowth.

Main Results:

• Combined MEK and CDK4/6 inhibition delayed tumor regrowth more effectively in immunocompetent mice.
• Patients progressing on combination therapy exhibited T-cell exclusion.
• MEKi increased tumor immunogenicity and CD8+ T cell recruitment, while CDK4/6i enhanced CD137L expression.
• CD8+ T cell depletion or CD137 blockade accelerated tumor regrowth during combination treatment.

Conclusions:

• Combined MEK and CDK4/6 inhibition elicits an antitumor immune response involving CD137L.
• Targeting both MEK and CDK4/6 pathways, alongside immune components, offers a potential therapeutic strategy for melanoma.