Antigen-Presenting Signaling Events in the Tumor Ecology Associate with Response to Anti-PD-1 Treatment in Lung Cancer

Immune-checkpoint blockade has emerged as a powerful therapeutic strategy in lung cancer. However, the molecular mechanisms associated with response are still poorly understood. Using lung cancer as a model system, we employed protein pathway activation mapping and multiplex immunofluorescence to explore pathway-centered signaling events and tumor-immune spatial interactions associated with response to Nivolumab. Signaling data were collected from laser dissected tumor epithelia and the surrounding tumor-stroma interface (TSI) of 28 lung cancer patients treated with Nivolumab using the Reverse Phase Protein Microarray. As expected, quantitative PD-L1 measurements associated with response to treatment. Pathway-centered analysis revealed increased TLR4-based signaling events, pro-inflammatory molecules, and tumor-associated antigens in patients that benefitted from treatment. CD68+/PD-L1+ antigen-presenting cells spatial distribution was also associated with response to treatment. Taken together, these results suggest that a tumor ecology that favors immune activation may play a primary role in modulating response to compounds targeting the tumor-immune axis.