Journal for ImmunoTherapy of Cancer (Nov 2023)

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

  • Manfred Wuhrer,
  • Louis Boon,
  • Di Wang,
  • Yvette van Kooyk,
  • Ernesto Rodriguez,
  • Joke M M Den Haan,
  • Nadine van Montfoort,
  • Sandra J van Vliet,
  • Kelly Boelaars,
  • Laura Goossens-Kruijssen,
  • Charlotte M de Winde,
  • Dimitri Lindijer,
  • Babet Springer,
  • Irene van der Haar Àvila,
  • Aram de Haas,
  • Laetitia Wehry,
  • Reina E Mebius

DOI
https://doi.org/10.1136/jitc-2023-007805
Journal volume & issue
Vol. 11, no. 11

Abstract

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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.