Martes, 21 de mayo de 2024

López-Gil JC, García-Silva S, Ruiz-Cañas L, Navarro D, Palencia-Campos A,...,Sainz B Jr. The Peptidoglycan Recognition Protein 1 confers immune evasive properties on pancreatic cancer stem cells

Gut. 2024 May 16

"We have discovered a new immune "Achilles' heel" for cancer stem cells, which we hope will one day develop into a new immunotherapy for pancreatic cancer" - Dr. Bruno Sainz Anding-

Summary:

Objective: Pancreatic ductal adenocarcinoma (PDAC) has limited therapeutic options, particularly with immune checkpoint inhibitors. Highly chemoresistant 'stem-like' cells, known as cancer stem cells (CSCs), are implicated in PDAC aggressiveness. Thus, comprehending how this subset of cells evades the immune system is crucial for advancing novel therapies.

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.

Why do you highlight this publication?

When we eliminate PGLYRP1 from tumor cells, we see that the immune system responds by attacking them, preventing the formation of the primary tumor and metastatic spread, highlighting a previously unidentified immune checkpoint. We are now developing therapies to block or eliminate this protein with the hope of being able to combine them with current treatments to more efficiently attack and eliminate cancer stem cells, the root of the tumor.