Abstract B110: Effector CD4 T cells convert transient responses to KRAS targeted therapy into long-term durable remissions in pancreatic cancer

Abstract

Pancreatic ductal adenocarcinoma is refractory to most therapies, including immunotherapies, where reinvigoration of CD8 T cells with immune checkpoint blockade is insufficient to induce long-term durable remissions. Direct inhibitors of KRAS are clinically promising, although acquired resistance is common. To test if immunotherapy can synergize with KRAS inhibition to achieve long-term durable remission, we modeled KRAS inhibitor (KRASi) response and relapse in mice by using poorly immunogenetic orthotopically implanted PDAC mouse models. Unlike chemotherapy or checkpoint blockade combinations, a computationally designed IL-21 cytokine mimic (21h10) developed in collaboration with David Baker’s lab leads to long-term durable remissions. These durable remissions were observed across multiple mouse models , in combination with multiple KRAS inhibitors (MRTX1133, daraxonrasib, adagrasib), and in tumors with acquired resistance to KRAS inhibition via YAP amplification. Neither CD8 T cells nor MHC class I expression on tumor cells were important for efficacy of KRAS inhibition and 21h10 immunotherapy. Instead cDC2-primed CD4 T cells producing IFNg were crucial. Single cell analysis of the tumor microenvironment revealed that 21h10 along with KRAS inhibitors induced dramatic expansion of Th1-polarized CD4 T cells, and we used Tbx21-/- mice lacking Th1 cells and Ifng-/- mice to confirm a requirement for IFNg-producing CD4 T cells . CD4 T cells do not kill tumor cells directly, as cancer cell lacking MHCII expression preserved complete response to the treatment. Phagocytic macrophages were induced both in vivo and in vitro in the presence of 21h10 and Th1-polarized CD4 T cells, suggesting that macrophages are orchestrated to phagocytose cancer cells. To determine whether 21h10 might have a similar mechanism of action in humans, we analyzed ex vivo culture of 21h10 with human PDAC infiltrating T cells by single cell transcriptional profiling and showed a strong induction of IFNG production and other genes related to T cell activation and loss of Tregs. 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 into durable remissions.