Genomic alterations in IFN-γ pathway underlie resistance to anti-CTLA-4 (Yervoy) therapy

This week journal Cell published a short "reverse translational" study conducted on small cohort of patients non-responsive to immunotherapy with anti-CTLA-4 antibody (ipilimumab, Yervoy) that  showed that genomic alterations in IFN-γ pathway in non-responder patients could underlie their resistance to immunotherapy.  

For this study the authors compared 12 patients who did not respond to ipilimumab therapy (non-responders) and 4 patients who did respond to ipilimumab therapy (responders). They found that "tumor samples from non-responders were found to have significantly more somatic mutations, including copy-number alterations (CNAs) and single-nucleotide variants (SNVs) of the IFN-γ pathway genes".

Next, the authors showed that primary melanoma cell lines derived from anti-CTLA-4 responder or non-responder patients could be differentiated based on their in vitro sensitivity to IFN-γ.

Next, they showed quite bizarre experiment. By knocking down IFN-γ receptor in mouse B16 melanoma cells the authors showed that these cell line became less sensitive to IFN-γ in vitro. Not sure about logic behind these experiment.  

Finally, the authors showed that B16 melanoma cells deficient for IFN-γ signaling and transplanted into WT mice were less sensitive to anti-CTLA-4 therapy.

In summary, this small cohort study suggests that screening of melanoma patients for genomic alterations in IFN-γ pathway could be useful in better predicting therapeutic outcome for this checkpoint inhibitor therapy.

David Usharauli