# Enhancing TIL populations and immunotherapy efficacy in melanoma by modulating fucosylation

> **NIH NIH R01** · H. LEE MOFFITT CANCER CTR & RES INST · 2021 · $457,861

## Abstract

PROJECT SUMMARY/ABSTRACT
Our immune system is crucial for recognizing and suppressing cancers in the body. Unfortunately, melanomas,
one of the most lethal skin cancers, can interact with and inactivate immune cells. Among the most effective
anti-melanoma therapies are immunotherapies that reactivate or “train” the anti-tumor activities of immune
cells. However, the effectiveness of immunotherapies is currently limited to ~30% of patients. Although the
underlying causes are unclear, lack of responsiveness in patients is associated with insufficient infiltration of
tumors by immune cells. Thus, studies aimed at elucidating melanoma:immune interactions and increasing the
immune infiltration of tumors are required to improve immunotherapies.
 We discovered a potential way to increase the efficacy of immunotherapies by boosting infiltration of
melanomas with tumor-suppressing immune cells using the plant sugar L-fucose. In a process called
fucosylation, cells used L-fucose to modify proteins, affecting their maturation/function. We found that
fucosylation is generally reduced during melanoma progression in humans, prompting us to test if increasing L-
fucose/fucosylation levels in melanomas elicits therapeutically beneficial effects. Simply feeding L-fucose to
melanoma-bearing mice reduces tumor growth and metastasis by >50% (Lau et al. Sci Signal 2015).
Intriguingly, those smaller tumors contain 10-50 times more tumor-infiltrating lymphocytes (“TIL”) than tumors
from mice not fed L-fucose. Genetically increasing the fucosylation of melanoma cells elicits the same effects,
suggesting that melanoma fucosylation triggers anti-tumor immunity. We determined that CD4+/CD25- T cells
are crucial for L-fucose-triggered recruitment of TILs including CD8+ T, NK, and DCs that suppress tumor
growth. We identified the immune-regulating protein HLA-DRB1 as fucosylated, and its expression is crucial for
TIL recruitment/tumor suppression, prompting our hypothesis that fucosylation of HLA-DRB1 triggers
CD4+/CD25- T cell-mediated TIL recruitment and suppression of melanoma. However, how fucosylation
regulates HLA-DRB1 to mediate anti-melanoma immunity, if those effects are due to increased tumor
immunogenicity, CD4+/CD25- T cell function, or both, and if L-fucose/fucosylation can enhance immunotherapy
efficacy or have prognostic utility is not known. We propose 3 Specific Aims (SAs) to test our hypothesis and
address these questions:
·SA1: Determine how fucosylation regulates the localization and immune function of HLA-DRB1
·SA2: Determine how systemic fucosylation affects CD4+/CD25- T cell biology.
·SA3: Determine if L-fucose/fucosylation enhances anti-PD1/TIL therapy and predicts patient prognosis
Our goal is to provide key biological/mechanistic insights into melanoma:immune interactions, which will
establish a basis for developing enhanced, fucosylation-based patient stratification and treatment strategies.

## Key facts

- **NIH application ID:** 10169386
- **Project number:** 5R01CA241559-03
- **Recipient organization:** H. LEE MOFFITT CANCER CTR & RES INST
- **Principal Investigator:** Eric Kirk Lau
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $457,861
- **Award type:** 5
- **Project period:** 2019-06-01 → 2024-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10169386

## Citation

> US National Institutes of Health, RePORTER application 10169386, Enhancing TIL populations and immunotherapy efficacy in melanoma by modulating fucosylation (5R01CA241559-03). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10169386. Licensed CC0.

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