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Effector CD4 T Cells Convert Transient Responses to KRAS-Targeted Therapy into Long-Term Durable Remissions in Pancreatic Cancer

Pancreatic ductal adenocarcinoma (PDAC) is refractory to most therapies, including immunotherapies in which reinvigoration of CD8 T cells is insufficient to induce durable long-term remissions. Direct KRAS inhibitors are clinically promising; however, acquired resistance is common. Using AI-assisted computational design, we developed a de novo IL-21 mimic, 21h10, with enhanced stability and high signaling potency in both humans and mice. Using an orthotopic PDAC mouse model, we evaluated responses and relapse following KRAS inhibitor treatment and demonstrated that, unlike combinations with chemotherapy or checkpoint blockade, the combination of 21h10 and KRAS inhibition is curative. Single-cell transcriptional profiling with TCR-seq revealed oligoclonal expansion of effector Th1-polarized CD4 T cells and depletion of Tregs. To evaluate the efficacy of 21h10 in human samples, we performed single-cell RNA-seq analyses on treatment-naive specimens following short-term ex vivo treatment with 21h10. This dataset consists of Illumina NovaSeq sequencing output (FASTQ files) generated from tumor libraries prepared using the 10x Genomics Single Cell 5′ Immune Profiling platform. FASTQ files are provided for gene expression (GEX), TCR, and, for multiplexed samples, HTO libraries.