# Dendritic Cell Proteoglycans and Reprogramming Cancer Immunity

> **NIH VA I01** · VA SAN DIEGO HEALTHCARE SYSTEM · 2021 · —

## Abstract

Early in cancer growth, metastases and dendritic cells (DCs) traffic to draining lymph nodes (DLN). In lung
cancer and other carcinomas, immune-suppression dominates a tumor microenvironment characterized by
immature DCs, weak T-effector responses, proliferation of T-regulatory cells (Tregs), and over-production of
immuno-suppressive cytokines. This heavily represses anti-tumor immunity. A high-impact area of new
scientific discovery is immunotherapy. We find dramatic clinical responses in some advanced-stage cancer
patients by blocking suppression of effector T cells. Only a fraction (<25%) of such patients, however, respond
with durable remissions. Preliminary work shows that a unique class of glycans known as heparan sulfate (HS)
drives subversive DC traffic and DC immaturity. While we have inhibited such DC traffic by targeting lymphatic
endothelial HS, new work suggests that DC-specific HS alterations may modulate both pathologic chemokine-
dependent DC traffic as well as DC maturation and function. New studies also show that these properties may
favorably impact anti-tumor T cell functions, with inhibition of tumor growth and progression. Herein we target
such glycans in tumor and cell-based studies, while studying immune-function and molecular mechanisms.
This proposal addresses the hypothesis that targeting HS glycans on the surface of DCs in lung cancer
through genetic means and novel inhibitors will inhibit DLN colonization by tolerogenic DCs and improve anti-
tumor immunity. Reduced immune-tolerance and improved tumor-antigen responses by more mature DCs,
with improved T cell induction will result in a novel endogenous anti-tumor state. To test this, we propose to:
(1) Characterize tumor growth and anti-tumor immunity in model antigen- as well as spontaneous lung
carcinoma models in mice bearing DC-glycan alterations. We will assess how a DC-targeted mutation in a key
sulfating HS biosynthetic enzyme (Ndst1) affects T cell immunity in tumors and thoracic DLN of mice with
orthotopic Ovalbumin-expressing Lewis lung carcinomas (LLC-Ova), including Ova-specific immunity and
effects on tumor growth. Immunity and tumor growth in a KRAS transgenic mutant model will also be studied.
(2) Study anti-tumor DC and T cell functions in ex-vivo preparations from lung carcinoma bearing mice with
DC-specific alterations in HS biosynthesis. DC maturation, antigen presentation, and the capacity of DCs from
LLC-Ova tumors grown in DC-targeted HS mutants to activate Ova-sensitized T cells will be examined, as will
tumor-cytolytic capacity of CD8+ T cells isolated from DLNs of tumor-bearing mutant vs control mice. Studies
will also include the effects of mutation on DLN colonization by plasmacytoid DCs and their functional capacity.
(3) Assess chemokine-receptor interactions and signaling mechanisms in the setting of DC-targeted alterations
in HS biosynthesis; and the effects of novel HS inhibitors on tumor growth and immunity. We will study how HS
mutation...

## Key facts

- **NIH application ID:** 10045943
- **Project number:** 5I01BX003688-04
- **Recipient organization:** VA SAN DIEGO HEALTHCARE SYSTEM
- **Principal Investigator:** MARK M FUSTER
- **Activity code:** I01 (R01, R21, SBIR, etc.)
- **Funding institute:** VA
- **Fiscal year:** 2021
- **Award amount:** —
- **Award type:** 5
- **Project period:** 2017-10-01 → 2022-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10045943

## Citation

> US National Institutes of Health, RePORTER application 10045943, Dendritic Cell Proteoglycans and Reprogramming Cancer Immunity (5I01BX003688-04). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10045943. Licensed CC0.

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