Background
Anti–PD-1 immunotherapy has demonstrated significant anti-tumor efficacy in relapsed or refractory NK/T-cell lymphoma (R/R NKTL), achieving an objective response rate (ORR) of approximately 40% to 60% for single-agent therapy, but resistance remains a substantial challenge.
Patients and Methods
We evaluated the efficacy of combining DNA methyltransferase (DNMT) inhibitors with anti–PD-1 mAb in 21 patients with R/R NKTL for whom has failed L-asparaginase–based regimens and prior anti–PD-1/PD-L1 therapy. To decipher the molecular mechanism of response to this combination therapy, we established a novel anti-PD-1–acquired resistant EL4 syngeneic xenograft model, a commonly used preclinical model for T-cell lymphoma. We profiled and deciphered the mechanisms of response and validate our findings in NKTL cell lines.
Results
This combination therapy achieved an objective response rate of 66.7% (14/21), with a complete response rate of 47.6% (10/21) and a 2-year overall survival rate of 50.2%. Preclinical models revealed that anti–PD-1 resistance was linked to the absence of CD8+ T-cell infiltration and suppressed IFN pathways. DNMT inhibitors reversed these effects, restoring CD8+ T-cell activities and tumor sensitivity to PD-1 blockade. Mechanistically, DNMT inhibitors triggered DNA demethylation of endogenous retroviral elements, activating viral mimicry via upregulated endogenous nucleic acids and type I IFN signaling, remodeling the tumor immune microenvironment and augmenting antitumor immunity.
Conclusions
These findings underscore DNMT inhibitors' role in overcoming PD-1 resistance and support their combination with anti–PD-1 as a promising strategy for R/R NKTL.
