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

Functional Cellular Anti-Tumor Mechanisms are Augmented by Genetic Proteoglycan Targeting. Neoplasia. 2019 Dec 30;22(2):86-97 Authors: Gupta P, Johns SC, Kim SY, El Ghazal R, Zuniga EI, Fuster MM Abstract 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 glyc...
Source: Neoplasia - Category: Cancer & Oncology Authors: Tags: Neoplasia Source Type: research