TY - JOUR
T1 - Unraveling the impact of sialic acids on the immune landscape and immunotherapy efficacy in pancreatic cancer
AU - Boelaars, Kelly
AU - Goossens-Kruijssen, Laura
AU - Wang, Di
AU - de Winde, Charlotte M.
AU - Rodriguez, Ernesto
AU - Lindijer, Dimitri
AU - Springer, Babet
AU - van der Haar Àvila, Irene
AU - de Haas, Aram
AU - Wehry, Laetitia
AU - Boon, Louis
AU - Mebius, Reina E.
AU - van Montfoort, Nadine
AU - Wuhrer, Manfred
AU - den Haan, Joke M. M.
AU - van Vliet, Sandra J.
AU - van Kooyk, Yvette
N1 - Funding Information: This work is financially supported by KWF VU2014-7200 to KB; SPINOZANWO SPI-93-538 to KB, LK, LW and YVK; LSH-TKI project DC4Balance LSM1806-SGFLSH-TKI to AdH; CMdW is supported by Cancer Center Amsterdam (grant no. CCA2019-9-57 and CCA2020-9-73). Publisher Copyright: © Author(s) (or their employer(s)) 2023.
PY - 2023/11/8
Y1 - 2023/11/8
N2 - 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.
AB - 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.
KW - Immunotherapy
KW - Lymphocytes, Tumor-Infiltrating
KW - Tumor Microenvironment
UR - http://www.scopus.com/inward/record.url?scp=85176461595&partnerID=8YFLogxK
U2 - https://doi.org/10.1136/jitc-2023-007805
DO - https://doi.org/10.1136/jitc-2023-007805
M3 - Article
C2 - 37940346
SN - 2051-1426
VL - 11
JO - Journal for Immunotherapy of Cancer
JF - Journal for Immunotherapy of Cancer
IS - 11
M1 - e007805
ER -