The Peptidoglycan Recognition Protein 1 confers immune evasive properties on pancreatic cancer stem cells.
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López-Gil Juan Carlos, García-Silva Susana, Ruiz-Cañas Laura, Navarro Diego, Palencia-Campos Adrián, Giráldez-Trujillo Antonio, Earl Julie, Dorado Jorge, Gómez-López Gonzalo, Monfort-Vengut Ana, Alcalá Sonia, Gaida Matthias M, García-Mulero Sandra, Cabezas-Sáinz Pablo, Batres-Ramos Sandra, Barreto Emma, Sánchez-Tomero Patricia, Vallespinós Mireia, Ambler Leah, Lin Meng-Lay, Aicher Alexandra, García García de Paredes Ana, de la Pinta Carolina, Sanjuanbenito Alfonso, Ruz-Caracuel Ignacio, Rodríguez-Garrote Mercedes, Guerra Carmen, Carrato Alfredo, de Cárcer Guillermo, Sánchez Laura, Nombela-Arrieta César, Espinet Elisa, Sanchez-Arevalo Lobo Víctor Javier, Heeschen Christopher, Sainz Bruno
Аннотация
DESIGN: We used the KPC mouse model (LSL-KrasG12D/+; LSL-Trp53R172H/+; Pdx-1-Cre) and primary tumour cell lines to investigate putative CSC populations. Transcriptomic analyses were conducted to pinpoint new genes involved in immune evasion. Overexpressing and knockout cell lines were established with lentiviral vectors. Subsequent in vitro coculture assays, in vivo mouse and zebrafish tumorigenesis studies, and in silico database approaches were performed.
RESULTS: Using the KPC mouse model, we functionally confirmed a population of cells marked by EpCAM, Sca-1 and CD133 as authentic CSCs and investigated their transcriptional profile. Immune evasion signatures/genes, notably the gene peptidoglycan recognition protein 1 (PGLYRP1), were significantly overexpressed in these CSCs. Modulating PGLYRP1 impacted CSC immune evasion, affecting their resistance to macrophage-mediated and T-cell-mediated killing and their tumourigenesis in immunocompetent mice. Mechanistically, tumour necrosis factor alpha (TNFα)-regulated PGLYRP1 expression interferes with the immune tumour microenvironment (TME) landscape, promoting myeloid cell-derived immunosuppression and activated T-cell death. Importantly, these findings were not only replicated in human models, but clinically, secreted PGLYRP1 levels were significantly elevated in patients with PDAC.
CONCLUSIONS: This study establishes PGLYRP1 as a novel CSC-associated marker crucial for immune evasion, particularly against macrophage phagocytosis and T-cell killing, presenting it as a promising target for PDAC immunotherapy.