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Acquired Resistance to Immunotherapy is Mediated by EMT and Irf6 Repression in Pancreatic Cancer

Article Alert: Acquired Resistance to Immunotherapy is Mediated by EMT and Irf6 Repression in Pancreatic Ductal Adenocarcinoma

 

Immune checkpoint blockade (ICB) has become a major component of cancer therapy, though durable clinical responses are difficult to achieve due to resistance. Primary resistance refers to cases that show no response and are attributable to intrinsic features of the tumor or tumor microenvironment (TME). Acquired resistance occurs after initial treatment success and develops over time in processes that involve cellular plasticity. Epithelial-mesenchymal transition (EMT) is the most characterized plasticity mechanism that induces alterations of cell identity and is associated with an immunosuppressive TME. However, tracing the successive events that lead to acquired resistance has been challenging due to the lack of an appropriate biological model.

A new study by Kim et al. reports the development of an immunotherapy-sensitive mouse model of pancreatic ductal adenocarcinoma (PDAC) to address the genesis of acquired ICB resistance (1). The authors used a combination immunotherapeutic regimen that induced various responses in mice, and produced tumor cell lines from these different cohorts for further experiments. They determined that EMT underlies ICB resistance in PDAC, with the EMT transcription factor genes Zeb1 and Snail being central to the resistance phenotype. Interestingly, characteristics of an immunosuppressive TME were not present in the resistant tumors. Overexpression of Zeb1/Snail in PDAC cells enhanced the mesenchymal phenotype and the resistance of PDAC cells to T cell killing. The researchers then used comparative transcriptional and chromatin interrogation strategies to find the key factor(s) associated with the defect in T cell killing and identified interferon regulatory factor 6 (Irf6). They went on to show that loss of Irf6 expression is indeed linked to acquired ICB therapy resistance as it results in decreased sensitivity of tumor cells to the pro-apoptotic actions of TNF-α, a phenotype that is reversible with Irf6 restoration. In summary, Kim et al. offer not only a mechanistic basis for how acquired resistance differs from primary resistance, but also indicate that targeting apoptotic pathways may be a way to surmount immunotherapy resistance.

GeneTex offers an extensive catalog of quality antibodies and reagents for cancer biology and epithelial-mesenchymal transition (EMT), which includes the Twist1/2 antibody (GTX127310) cited in the Kim et al. study. For more information, please see the product images below and visit www.genetex.com.

 

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Reference:

  1. Nat Commun. 2024 Feb 20;15(1):1532. doi: 10.1038/s41467-024-46048-7.