Unraveling the impact of sialic acids on the immune landscape and immunotherapy efficacy in pancreatic cancer

Boelaars, K.; Goossens-Kruijssen, L.; Wang, D.; Winde, C.M. de; Rodriguez, E.; Lindijer, D.; ... ; Kooyk, Y. van (2023)

Article / Letter to editor

Background Pancreatic ductal adenocarcinoma (PDAC) is one of the deadliest cancers. Despite the successful application of immune checkpoint blockade in a range of human cancers, immunotherapy in PDAC remains unsuccessful. PDAC is characterized by a desmoplastic, hypoxic and highly immunosuppressive tumor microenvironment (TME), where T-cell infiltration is often lacking (immune desert), or where T cells are located distant from the tumor islands (immune excluded). Converting the TME to an immune-inflamed state, allowing T-cell infiltration, could increase the success of immunotherapy in PDAC.

Method In this study, we use the KPC3 subcutaneous PDAC mouse model to investigate the role of tumor-derived sialic acids in shaping the tumor immune landscape. A sialic acid deficient KPC3 line was generated by genetic knock-out of the CMAS (cytidine monophosphate N-acetylneuraminic acid synthetase) enzyme, a critical enzyme in the synthesis of sialic acid-containing glycans. The effect of sialic acid-deficiency on immunotherapy efficacy was assessed by treatment with anti-programmed cell death protein 1 (PD-1) and agonistic CD40.

Result The absence of sialic acids in KPC3 tumors resulted in increased numbers of CD4⁺ and CD8⁺ T cells in the TME, and reduced frequencies of CD4⁺ regulatory T cells (Tregs) within the T-cell population. Importantly, CD8⁺ T cells were able to infiltrate the tumor islands in sialic acid-deficient tumors. These favorable alterations in the immune landscape sensitized sialic acid-deficient tumors to immunotherapy, which was ineffective in sialic acid-expressing KPC3 tumors. In addition, high expression of sialylation-related genes in human pancreatic cancer correlated with decreased CD8⁺ T-cell infiltration, increased presence of Tregs, and poorer survival probability.

Conclusion Our results demonstrate that tumor-derived sialic acids mediate T-cell exclusion within the PDAC TME, thereby impairing immunotherapy efficacy. Targeting sialic acids represents a potential strategy to enhance T-cell infiltration and improve immunotherapy outcomes in PDAC.

• Tumor Microenvironment
• Immunotherapy
• Lymphocytes, Tumor-Infiltrating

• All authors: Boelaars, K.; Goossens-Kruijssen, L.; Wang, D.; Winde, C.M. de; Rodriguez, E.; Lindijer, D.; Springer, B.; Avila, I.V.; Haas, A. de; Wehry, L.; Boon, L.; Mebius, R.E.; Montfoort, N. van; Wuhrer, M.; Haan, J.M.M. den; Vliet, S.J. van; Kooyk, Y. van
• Date: 2023-11-01
• Journal: Journal for ImmunoTherapy of Cancer
• Volume: 11
• Issue: 11
• DOI: doi:10.1136/jitc-2023-007805
• Link: https://jitc.bmj.com/content/11/11/e007805