Abstract
Authors
Erin M. Dickey, Harper M. Marsh, Camilla Rydberg-Millrud, Haleh Amirian, Karthik Rajkumar, Manan Patel, Andrew Adams, Anuroop Allena, Kevin Van der Jeught, Nipun Merchant, Peter J. Hosein, Anna Bianchi, David Liberg, Jashodeep Datta
Figure 1
IL1RAP-expressing myeloid-stromal networks are a therapeutic barrier in PDAC.
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(A ) UMAP of 654,997 cells from HTAN PDAC dataset (n = 79); IL1RAP expression across immune, stromal, and tumor-cell compartments in naive (n = 7), FOLFIRINOX-sensitive (FFX-sensitive) (n = 5), and resistant (n = 3) subgroups. (B ) CANFOUR trial: nadunolimab (Nadu) + gemcitabine/nab-paclitaxel (GnP) in metastatic PDAC; stromal/CAF and immune IL1RAP quantification from tumor biopsies (n = 49; top). Duration of response to nadunolimab + GnP stratified by stromal (n = 24, HR: 0.41;95%CI, 0.18–0.94) or immune (n = 19, HR: 0.36; 95%CI, 0.13–1.02) IL1RAP IHC (2-tailed log-rank test, right). (C ) UMAP of scRNA-seq clusters from PKT tumors showing IL1RAP gene module (Il1rap/Il1r1/Il1rl2/Il1rl1 ). (D ) PKT mice treated with mNadu or isotype; tumor volumes shown (n = 11/group). (E ) FACS quantification of CD11b+ myeloid and CD3+ T cell frequencies (%CD45+) in PKT tumors (n = 11/group, 2-tailed t test). (F ) Immunofluorescence of paired PDAC biopsies pre/postnadunolimab ± GnP. Scale bar: 100 μm. (G ) FACS of CD8+PD1hiCD44+ T cells by Ly108/CD69 status, indicating memory progenitor-exhausted and terminally exhausted (n = 11/group, 2-tailed t test). (H and I ) UMAP of 15,834 scRNA-seq profiles and pathway enrichment in myeloid (left) and T cell (right) single-cell clusters, from isotype vs. mNadu-treated PKT tumors (n = 3/group; FDR q < 0.05). (J ) Schema and survival of PKT mice treated with isotype, mNadu, GP + anti-PD1, or mNadu + GP + anti-PD1 (n = 8/group).* P < 0.05, **P = < 0.01, ***P < 0. 001.
