Effector CD4 T cells convert transient responses to KRAS targeted therapy into long term durable remissions in pancreatic cancer

ABSTRACT: Pancreatic ductal adenocarcinoma (PDAC) is refractory to most therapies, including immunotherapies where reinvigoration of CD8 T cells is insufficient to induce long-term durable remissions. Direct inhibitors of KRAS are clinically promising although acquired resistance is common. Interleukin-21 is a plieotropic cytokine with potential to augment anti-tumor immunity. Using AI-assisted computational design, we developed a de novo IL-21 mimic, 21h10, which displays augmented stability and high signaling potency in both humans and mice. We modeled KRAS inhibitor response and relapse in mice with orthotopic PDAC and show that - unlike chemotherapy or checkpoint blockade combinations - combination of 21h10 with KRASi is curative. Efficacy of 21h10 in PDAC is not dependent on CD8 T cells or MHC class I expression by the tumor. Single cell transcriptional profiling with TCRseq reveals oligoclonal expansion of effector Th1 polarized CD4 T cells and loss of Tregs. We show that cDC2-primed, tumor-specific CD4 T cells produce IFNg that acts on macrophages to clear tumor cells. CD4 T cells from blood of patients with PDAC respond robustly to 21h10. Similarly, short-term ex vivo culture of 21h10 with human PDAC induces IFNg production from infiltrating T cells. Thus IL-21-elicited CD4 T cells exert anti-tumor activity in mice and potentially in humans which can convert transient responses to KRAS inhibition to durable remissions.

ORGANISM(S): Mus musculus

PROVIDER: GSE307192 | GEO | 2026/09/22

REPOSITORIES: GEO