# Glycocalyx Targeting and Augmenting Cellular Immunity in Lung Cancer

> **NIH VA I01** · VA SAN DIEGO HEALTHCARE SYSTEM · 2023 · —

## Abstract

In lung cancer, tumor immunity is fueled by antigen presenting cells (APCs). We found that targeting glycans
on dendritic immune cells (DCs, as “professional” APCs) boosts CD8+ T cell influx and tumor cytolysis, likely
via augmented presentation of tumor antigens (Ag) on DCs. Augmenting continuous tumor Ag sensing via this
“endogenous” tumor microenvironment (TME) system may improve the specificity and magnitude of anti-tumor
immunity. In Merit work, we discovered how genetic targeting of unique DC glycans boosts anti-tumor T cell
responses, at least in part via Ag presentation mechanisms. We here build on initial insights. An advantage to
facilitating this process is that the “epicenter” for tumor Ag recognition (i.e., MHC/Ag - T-cell receptor axis) may
respond to dynamic Ag changes (including new mutations) to sustain tumor-cytotoxic CD8+ T cells in the TME.
Current immune-checkpoint therapy in advanced-stage lung cancer shows durable remissions that are limited
(<25%), and autoimmune toxicity poses serious challenges. We hypothesize that altering glycan fine structure
(proteoglycan under-sulfation or sialic acid inhibition) on the APC glycocalyx will boost Ag presentation and
augment anti-tumor T cell responses. To study this, with novel inhibitor strategies, we propose Aims as follows:
Study how targeting glycocalyx composition on key APCs from the TME augments anti-tumor T cell responses,
and test how genetic under-sulfation and under-sialylation of the lung APC glycocalyx affects tumor growth
inhibition and specific anti-tumor T-cell responses, including in vivo T cell proliferation and infiltration (Aim 1).
This will involve altering the fine structure of heparan sulfate or inhibiting sialic acid glycans that repress APC
effector functions in the TME. We will examine CD8+ T cell proliferation, activation, and tumor cytolysis in the
setting of APC-targeted glycan inhibition in tumor models with Ag-responsive T cell reporting systems. Studies
will include characterizing how mutation affects tolerance/exhaustion signatures in DCs purified from the lung
TME. We also study lymphatic glycan targeting to transform lymphatic endothelium into a novel APC platform.
Discover mechanisms by which glycan structural changes promote spatial and temporal display of MHC/Ag on
tumor DCs, and study how this augments engagement with the T cell receptor (TcR) using model Ag and
transgenic T cells (Aim 2). We will study how DC glycocalyx mutations in the fine structure of heparan sulfate
and sialic acid affect Ag presentation by tumor-Ag sensitized DCs or ex-vivo marrow DCs pulsed with model
Ag. We will also study how such mutations on model Ag systems affect TcR interactions with DC MHC-I/Ag
using novel proximity ligation technology. Beyond these approaches, we will measure MHC-I/Ag internalization
on the DC surface in the setting of glycocalyx targeting strategies. We will include parallel studies on tumor
lymphatic endothelial cells as unique APCs in Ag-prese...

## Key facts

- **NIH application ID:** 10650162
- **Project number:** 5I01BX003688-06
- **Recipient organization:** VA SAN DIEGO HEALTHCARE SYSTEM
- **Principal Investigator:** MARK M FUSTER
- **Activity code:** I01 (R01, R21, SBIR, etc.)
- **Funding institute:** VA
- **Fiscal year:** 2023
- **Award amount:** —
- **Award type:** 5
- **Project period:** 2017-10-01 → 2026-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10650162

## Citation

> US National Institutes of Health, RePORTER application 10650162, Glycocalyx Targeting and Augmenting Cellular Immunity in Lung Cancer (5I01BX003688-06). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10650162. Licensed CC0.

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