This Endeavor Award addresses a major challenge in gastroesophageal adenocarcinoma (GEA): why many tumors resist immune checkpoint blockade despite the incorporation of anti-PD-1 therapy into standard treatment. Outcomes for patients with advanced disease remain poor, and combination immunotherapy approaches have not produced a substantial additional benefit. The investigators have identified tumor-intrinsic activation of the NLRP3 inflammasome as a potential driver of this resistance, linking NLRP3 activity and amplification to immune suppression and inferior treatment response.
The multidisciplinary team will investigate how NLRP3 amplification shapes GEA biology, the tumor immune microenvironment, and clinical outcomes. Patient tumor and blood samples will be analyzed using genomic, transcriptomic, spatial, and immune-profiling approaches to characterize NLRP3 amplification and determine whether extrachromosomal DNA enables tumors to rapidly increase NLRP3 copy number under therapeutic stress. The researchers will also examine how NLRP3 amplification suppresses antitumor immunity, including its effects on MHC class I antigen presentation, T cell activity, and recruitment of immunosuppressive myeloid cells.
The project will then translate these mechanistic insights into new therapeutic strategies. Using patient-derived GEA organoids, the team will test whether NLRP3-amplified tumors are particularly sensitive to pharmacologic NLRP3 inhibition. They will also combine proteomic analysis with CRISPR screening to identify tumor-specific regulators of NLRP3 that could be targeted while preserving beneficial inflammasome functions in normal immune cells.
By connecting inflammatory signaling, genomic plasticity, and immune escape, this work could establish NLRP3 amplification as both a biomarker and a therapeutic vulnerability in GEA. Ultimately, the findings could guide patient selection and provide the foundation for clinical trials combining NLRP3-directed therapies with checkpoint blockade and chemotherapy, with the goal of improving outcomes for patients whose cancers currently resist immunotherapy.