Targeting adenosine enhances immunotherapy in MSS colorectal cancer with EGFRvIII mutation

Area of Science:

• Oncology
• Immunotherapy
• Cancer Genomics

Background:

• Microsatellite stable colorectal cancer (MSS CRC) often resists immunotherapy.
• Epidermal growth factor receptor (EGFR)-targeted therapies show potential but require better patient stratification for enhanced immunotherapy.
• Inadequate patient selection may explain the limited clinical benefit of current immunotherapies in MSS CRC.

Purpose of the Study:

• To identify a distinct subtype of MSS CRC that benefits from combination therapy.
• To investigate the role of EGFR variant type III (EGFRvIII) in MSS CRC immunotherapy resistance.
• To explore the efficacy of combining adenosine inhibition with anti-PD-1 therapy in EGFRvIII-mutated MSS CRC.

Main Methods:

• Analysis of circulating tumor cells and tumor tissues from MSS CRC patients treated with cetuximab.
• Assessment of EGFRvIII expression and immune infiltration in patient samples.
• Utilizing syngeneic mouse models of EGFRvIII CRC to test combined adenosine inhibition and anti-PD-1 therapy.

Main Results:

• EGFRvIII mutations, present in ~10% of MSS CRC, correlate with poor response to cetuximab.
• EGFRvIII-mutated MSS CRC exhibits an adenosine-driven immunosuppressive tumor microenvironment (TME).
• Combination therapy with adenosine inhibitors and anti-PD-1 reversed cetuximab resistance and improved anti-PD-1 efficacy in EGFRvIII CRC models.

Conclusions:

• EGFRvIII-positive MSS CRC is identified as a unique subtype with an immunosuppressive TME mediated by adenosine.
• Targeting adenosine significantly enhances anti-PD-1 efficacy in MSS CRC, particularly in the EGFRvIII-mutated subtype.
• This study highlights a novel therapeutic strategy for a subset of immunotherapy-resistant colorectal cancer.