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Published on: November 19, 2019
Targeting Oncomucin-Driven Immunosuppression Improves the Efficacy of K-rasG12D Inhibition in Pancreatic Cancer
Namita Bhyravbhatla1, Zahraa W Alsafwani1, Ishwor Thapa2
1Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, Nebraska.
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.
Insights
Oncogenic mucins (oncoMUCs) drive pancreatic cancer immune evasion. Targeting these oncoMUCs enhances K-ras inhibitor efficacy, offering new therapeutic strategies for pancreatic ductal adenocarcinoma (PDA).
Area of Science:
- Oncology
- Immunology
- Molecular Biology
Background:
- Oncogenic de novo mucins (oncoMUCs), including MUC4, MUC16, and MUC5AC, are upregulated in pancreatic ductal adenocarcinoma (PDA).
- While individual oncoMUC functions are known, their collective role in PDA progression and the tumor microenvironment (TME) is unclear.
- Understanding the patient-centric impact of oncoMUCs on the TME is crucial for developing diagnostic and therapeutic strategies.
Purpose of the Study:
- To investigate the collective impact of oncoMUCs on PDA progression and the TME.
- To elucidate the mechanisms by which oncoMUCs contribute to immune suppression.
- To evaluate the therapeutic potential of targeting oncoMUCs in combination with K-ras inhibitors.
Main Methods:
- Integration of single-cell RNA sequencing, multiplex immunostaining, and murine models to characterize the oncomucinome.
- NanoString profiling and gene silencing to investigate immune suppression.
- Evaluation of pharmacologic oncoMUC targeting in combination with a K-rasG12D inhibitor in a syngeneic murine model.
Main Results:
- OncoMUCs exhibit clonal diversity and are associated with a survival disadvantage in PDA.
- Deletion of oncoMUC4 and oncoMUC16 subpopulations reduced immune checkpoint expression (VISTA, TIM3) and increased CD8+ T-cell and antigen-presenting cell infiltration.
- OncoMUCs potentiate EGFR and UNC5B signaling, leading to upregulation of immune checkpoints (ICs), VISTA, and PD-L1.
- Targeting oncoMUCs enhanced the efficacy of K-rasG12D inhibition (MRTX1133), reducing tumor burden and ICs.
Conclusions:
- Transmembrane oncoMUCs promote immune evasion in PDA via EGFR/UNC5B signaling.
- Targeting oncoMUCs can overcome resistance to K-rasG12D inhibition.
- OncoMUCs represent novel immune regulators and potential therapeutic targets in PDA.
