Dihydropyrimidine dehydrogenase modulates immune response to checkpoint inhibition in mismatch repair deficient/microsatellite instability-high colorectal cancer.

BACKGROUND

Treatment with immune checkpoint inhibitors (ICIs) has radically improved outcomes for patients with microsatellite instability-high (MSI-H) metastatic colorectal cancer (mCRC). Intrinsic and acquired resistance, however, remains an important concern. Pyrimidine pathway regulates the innate immune response and may offer an opportunity to enhance ICI efficacy via modulation of pyrimidine metabolism. Identification of primary, adaptive and acquired resistance mechanisms and development of actionable strategies to overcome resistance and expand the benefit of ICI is paramount. Our group is the first to show that the dihydropyrimidine dehydrogenase (DPD; gene DPYD) metabolic pathway predicts the efficacy of ICI in MSI-H tumors.

METHODS

Retrospective analysis of germline single nucleotide polymorphisms was done in patients with MSI-H CRC cohort (Veneto Institute of Oncology; OIOV-IRCCS, Padua, Italy) treated with immunotherapy. Dpyd knockout or overexpressed MC38 MSI-H syngeneic mice models were treated with anti-programmed cell death protein 1 (PD-1) and anti-cytotoxic T-lymphocyte associated protein 4 (CTLA-4) alone or in combination and their effect on tumor growth and its microenvironment was studied.

RESULTS

In our real-world data analysis, genetic variants in DPYD were associated with progression-free survival and tumor response in patients with MSI-H mCRC treated with ICI. In preclinical studies, complete tumor elimination was observed in 100% of mice bearing Dpyd knockout tumors treated with a combination of anti-PD-1 and anti-CTLA-4, further validated by pharmacologically inhibiting DPD using eniluracil.

CONCLUSION

Our results showed that the pyrimidine pathway has a strong association with immunotherapy treatment response in CRC. These findings may support the development of novel treatment strategies exploiting DPD inhibition in MSI-H tumors and their quick integration into clinic.