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Functional Cellular Anti-Tumor Mechanisms are Augmented by Genetic Proteoglycan Targeting.

Publication ,  Journal Article
Gupta, P; Johns, SC; Kim, SY; El Ghazal, R; Zuniga, EI; Fuster, MM
Published in: Neoplasia
February 2020

While recent research points to the importance of glycans in cancer immunity, knowledge on functional mechanisms is lacking. In lung carcinoma among other tumors, anti-tumor immunity is suppressed; and while some recent therapies boost T-cell mediated immunity by targeting immune-checkpoint pathways, robust responses are uncommon. Augmenting tumor antigen-specific immune responses by endogenous dendritic cells (DCs) is appealing from a specificity standpoint, but challenging. Here, we show that restricting a heparan sulfate (HS) loss-of-function mutation in the HS sulfating enzyme Ndst1 to predominantly conventional DCs (Ndst1f/f CD11cCre+ mutation) results in marked inhibition of Lewis lung carcinoma growth along with increased tumor-associated CD8+ T cells. In mice deficient in a major DC HS proteoglycan (syndecan-4), splenic CD8+ T cells showed increased anti-tumor cytotoxic responses relative to controls. Studies examining Ndst1f/f CD11cCre + mutants revealed that mutation was associated with an increase in anti-tumor cytolysis using either splenic CD8+ T cells or tumor-infiltrating (TIL) CD8+ T cells purified ex-vivo, and tested in pooled effector-to-target cytolytic assays against tumor cells from respective animals. On glycan compositional analysis, HS purified from Ndst1f/f CD11cCre + mutant DCs had reduced overall sulfation, including reduced sulfation of a tri-sulfated disaccharide species that was intriguingly abundant on wildtype DC HS. Interestingly, antigen presentation in the context of major histocompatibility complex class-I (MHC-I) was enhanced in mutant DCs, with more striking effects in the setting of HS under-sulfation, pointing to a likely regulatory role by sulfated glycans at the antigen/MHC-I - T-cell interface; and possibly future opportunities to improve antigen-specific T cell responses by immunologic targeting of HS proteoglycans in cancer.

Duke Scholars

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Published In

Neoplasia

DOI

EISSN

1476-5586

Publication Date

February 2020

Volume

22

Issue

2

Start / End Page

86 / 97

Location

United States

Related Subject Headings

  • T-Lymphocytes
  • Sulfotransferases
  • Proteoglycans
  • Polysaccharides
  • Oncology & Carcinogenesis
  • Mice
  • Major Histocompatibility Complex
  • Lymphocytes, Tumor-Infiltrating
  • Loss of Function Mutation
  • Immunity, Cellular
 

Citation

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ICMJE
MLA
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Gupta, P., Johns, S. C., Kim, S. Y., El Ghazal, R., Zuniga, E. I., & Fuster, M. M. (2020). Functional Cellular Anti-Tumor Mechanisms are Augmented by Genetic Proteoglycan Targeting. Neoplasia, 22(2), 86–97. https://doi.org/10.1016/j.neo.2019.11.003
Gupta, Purva, Scott C. Johns, So Young Kim, Roland El Ghazal, Elina I. Zuniga, and Mark M. Fuster. “Functional Cellular Anti-Tumor Mechanisms are Augmented by Genetic Proteoglycan Targeting.Neoplasia 22, no. 2 (February 2020): 86–97. https://doi.org/10.1016/j.neo.2019.11.003.
Gupta P, Johns SC, Kim SY, El Ghazal R, Zuniga EI, Fuster MM. Functional Cellular Anti-Tumor Mechanisms are Augmented by Genetic Proteoglycan Targeting. Neoplasia. 2020 Feb;22(2):86–97.
Gupta, Purva, et al. “Functional Cellular Anti-Tumor Mechanisms are Augmented by Genetic Proteoglycan Targeting.Neoplasia, vol. 22, no. 2, Feb. 2020, pp. 86–97. Pubmed, doi:10.1016/j.neo.2019.11.003.
Gupta P, Johns SC, Kim SY, El Ghazal R, Zuniga EI, Fuster MM. Functional Cellular Anti-Tumor Mechanisms are Augmented by Genetic Proteoglycan Targeting. Neoplasia. 2020 Feb;22(2):86–97.
Journal cover image

Published In

Neoplasia

DOI

EISSN

1476-5586

Publication Date

February 2020

Volume

22

Issue

2

Start / End Page

86 / 97

Location

United States

Related Subject Headings

  • T-Lymphocytes
  • Sulfotransferases
  • Proteoglycans
  • Polysaccharides
  • Oncology & Carcinogenesis
  • Mice
  • Major Histocompatibility Complex
  • Lymphocytes, Tumor-Infiltrating
  • Loss of Function Mutation
  • Immunity, Cellular