ICB Response Is Associated with Pretreatment STAT1 Activation

Response to immune checkpoint blockade (ICB) in cancer is highly variable, with some patients experiencing rapid recovery and others exhibiting no response. Some predictors of response to ICB have been reported, but none fully explain the differences. Using two mouse models, Zemek and colleagues found differences in the pretreatment microenvironment that correlated with response to ICB. Specifically, mice were inoculated bilaterally, allowing one tumor to be removed for analysis prior to treatment while the other's response to ICB with anti–PD-L1 and anti–CTLA4 was evaluated after treatment. Bulk and single-cell RNA sequencing along with flow cytometry revealed marked differences in gene regulation between ICB responders and nonresponders, with genes associated with type I and II interferon responses and inflammation enriched in responsive tumors in both mouse models. These gene sets were also enriched in patients with urothelial cancer who responded to the PD-L1 antibody atezolizumab. Weighted gene correlation network analysis identified signal transducer and activator of transcription 1 (Stat1) as a hub, and responsive tumors had greater proportions of cells with active (phosphorylated) STAT1. In both models, responding tumors had a greater proportion of natural killer (NK) cells, and depletion of NK cells prior to treatment revealed that NK cells were required for response to ICB. Pretreatment of mice with a combination of three treatments targeting regulators associated with ICB response in the pathway analysis—including IFNγ, anti–IL10, and the Toll-like receptor agonist poly(I:C)—resulted in a substantial improvement, from 0% to 10% response with ICB alone to up to 80% response in the pretreated group. Pretreatment increased the frequencies of NK cells, the presence of which was required for the improved ICB response. These results provide new biomarkers for response to ICB that could be used to help determine which patients will be immediate responders and which require pretreatment with other therapies to benefit from ICB.

Zemek RM, De Jong E, Chin WL, Schuster IS, Fear VS, Casey TH, et al. Sensitization to immune checkpoint blockade through activation of a STAT1/NK axis in the tumor microenvironment. Sci Transl Med 2019:11;eaav7816.

Note: Research Watch is written by Cancer Discovery editorial staff. Readers are encouraged to consult the original articles for full details. For more Research Watch, visit Cancer Discovery online at http://cancerdiscovery.aacrjournals.org/CDNews.