Gastroenterology · 2026
Targeting Oncomucin-Driven Immunosuppression Improves the Efficacy of K-rasG12D Inhibition in Pancreatic Cancer.
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Bhyravbhatla Namita, Alsafwani Zahraa W, Thapa Ishwor, Nallasamy Palanisamy, Atri Pranita, Moran Segura Carlos M, Park Margaret A, Khan Imran, Villalobos-Ayala Krystal, Marimuthu Saravanakumar, Cox Jesse L, Centeno Barbara A, Aithal Abhijit, Malafa Mokenge, Ghersi Dario, Batra Surinder K, Kumar Sushil
Аннотация
BACKGROUND & AIMS: Oncogenic de novo mucins (oncoMUCs; MUC4, MUC16, and MUC5AC) are progressively upregulated in pancreatic ductal adenocarcinoma (PDA). Although their individual cell-intrinsic roles have been investigated, their collective impact on PDA progression and the tumor microenvironment (TME) remains unclear. Evaluating the patient-centric impact of oncoMUCs on the TME will inform diagnostic and therapeutic strategies.
METHODS: Integration of single-cell RNA sequencing (n = 34), multiplex/sequential immunostaining, and murine models characterized the oncomucinome. Immune suppression was investigated using NanoString profiling and gene silencing. Pharmacologic oncoMUC targeting (Istradefylline) was evaluated in combination with K-rasG12D inhibitor in a syngeneic murine model.
RESULTS: OncoMUCs showed extensive clonal diversity and survival disadvantage (P = .00013) in PDA. OncoMUC4 and oncoMUC16 subpopulations were enriched after stage IIA/B, and their deletion significantly reduced immune checkpoints (ICs) expression (V-domain immunoglobulin suppressor of T-cell activation [VISTA]: P < .0001, .001; T-cell immunoglobulin and mucin domain-containing protein 3 [TIM3]: P < .0001, .001), and increased CD8+ T-cell (P = .0087) and antigen-presenting cell infiltration (macrophages: P < .004; dendritic cells: P = .021) in tumors of PDA autochthonous models. Mechanistically, these subpopulations potentiate epidermal growth factor receptor (EGFR) and Unc-5 Netrin Receptor B (UNC5B) signaling, which collaboratively upregulate ICs, VISTA, and programmed death ligand 1 ([PD-L1] P < .0001). As KrasG12D inhibition (MRTX1133) upregulated oncoMuc4 and oncoMuc16 expression, pharmacological targeting of oncoMUCs enhanced the efficacy of MRTX1133, as indicated by reduced tumor burden (P = .034), ICs (local, [P range 0.03-0.009] and systemic VISTA and TIM3 [P = .024, .014]), and Unc5b (P = .048) expression.
CONCLUSIONS: Transmembrane oncoMUCs promote immune evasion in PDA through EGFR/UNC5B signaling, and their targeting enhances the efficacy of K-rasG12D inhibition, suggesting oncoMUCs as novel immune regulators and therapeutic targets in PDA.
METHODS: Integration of single-cell RNA sequencing (n = 34), multiplex/sequential immunostaining, and murine models characterized the oncomucinome. Immune suppression was investigated using NanoString profiling and gene silencing. Pharmacologic oncoMUC targeting (Istradefylline) was evaluated in combination with K-rasG12D inhibitor in a syngeneic murine model.
RESULTS: OncoMUCs showed extensive clonal diversity and survival disadvantage (P = .00013) in PDA. OncoMUC4 and oncoMUC16 subpopulations were enriched after stage IIA/B, and their deletion significantly reduced immune checkpoints (ICs) expression (V-domain immunoglobulin suppressor of T-cell activation [VISTA]: P < .0001, .001; T-cell immunoglobulin and mucin domain-containing protein 3 [TIM3]: P < .0001, .001), and increased CD8+ T-cell (P = .0087) and antigen-presenting cell infiltration (macrophages: P < .004; dendritic cells: P = .021) in tumors of PDA autochthonous models. Mechanistically, these subpopulations potentiate epidermal growth factor receptor (EGFR) and Unc-5 Netrin Receptor B (UNC5B) signaling, which collaboratively upregulate ICs, VISTA, and programmed death ligand 1 ([PD-L1] P < .0001). As KrasG12D inhibition (MRTX1133) upregulated oncoMuc4 and oncoMuc16 expression, pharmacological targeting of oncoMUCs enhanced the efficacy of MRTX1133, as indicated by reduced tumor burden (P = .034), ICs (local, [P range 0.03-0.009] and systemic VISTA and TIM3 [P = .024, .014]), and Unc5b (P = .048) expression.
CONCLUSIONS: Transmembrane oncoMUCs promote immune evasion in PDA through EGFR/UNC5B signaling, and their targeting enhances the efficacy of K-rasG12D inhibition, suggesting oncoMUCs as novel immune regulators and therapeutic targets in PDA.