# Metabolic and Effector Properties of invariant Natural Killer T cells in Neuroblastoma

> **NIH NIH F31** · UNIVERSITY OF PENNSYLVANIA · 2020 · $32,690

## Abstract

PROJECT SUMMARY
Neuroblastoma (NB) is an early childhood tumor of the developing sympathetic nervous system that
contributes to approximately 15% of childhood cancer-related deaths. Survival rates for the high-risk form of
the disease remain at under 50%, emphasizing the critical need for more effective therapies. T-cell based
immunotherapies have shown promising results in hematopoietic malignancies, but in solid tumors like NB, the
nutrient-poor, immunosuppressive tumor microenvironment (TME) limits the effector function of these
lymphocytes. Thus it is imperative to understand how lymphocytes adapt to the TME in order to harness their
anti-tumor activity for developing more effective immunotherapies. Using an autochthonous, immunocompetent
murine model of high-risk NB (TH-MYCN+/+), our lab identified a significant population of intratumoral invariant
natural killer T (iNKT) cells relative to conventional T cells (TCONV), suggesting that iNKT cells may harbor
unique features enabling survival in the TME. iNKT cells possess phenotypic and functional features of both
innate natural killer cells and memory T cells and engage a number of anti-tumor immune pathways. However,
their function in the TME is largely unknown. In TCONV, metabolism and effector function are tightly linked. Upon
stimulation, naïve and memory T cells shift from oxidative metabolism to rely on glycolysis as they differentiate
into effector T cells. However, in the TME, TCONV must compete for limited glucose supplies, placing
bioenergetic constraints that limit their anti-tumor function. Indeed, oxidative metabolism enables long-term
survival and persistence of TCONV. In contrast, the metabolic properties of iNKT cells are not known, and may
provide critical insight into their anti-tumor functions in the TME. Our preliminary analysis suggests that in vitro
stimulated iNKT cells uptake less glucose than TCONV, suggesting that iNKT cells may have unique metabolic
properties that confer enhanced effector function in the TME. I hypothesize that iNKT cells are uniquely
capable of adapting to the TME by relying predominantly on oxidative metabolism, enabling sustained anti-
tumor effector function. In Aim 1, I will define the metabolic profiles (1a) and functional properties (1b) of iNKT
cells stimulated in TME-like conditions in vitro to assess the individual contributions of glucose and oxygen
deprivation on their metabolic and anti-tumor activity relative to TCONV. In Aim 2, I will use a conjugate molecule
that fuses an iNKT cell activating ligand to an NB-specific antigen to specifically activate iNKT cells in the
murine NB TME and assess the frequency, proliferation, metabolism, and functional features of these iNKT
cells (2a) and determine whether this activation of intratumoral iNKT cells controls NB growth and prolongs
survival of TH-MYCN+/+ mice. Collectively, the proposed studies will define novel cellular properties of iNKT
cells and determine contexts in which iNKT cells ...

## Key facts

- **NIH application ID:** 9949672
- **Project number:** 5F31CA232468-03
- **Recipient organization:** UNIVERSITY OF PENNSYLVANIA
- **Principal Investigator:** Priya Khurana
- **Activity code:** F31 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $32,690
- **Award type:** 5
- **Project period:** 2018-07-16 → 2021-07-15

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9949672

## Citation

> US National Institutes of Health, RePORTER application 9949672, Metabolic and Effector Properties of invariant Natural Killer T cells in Neuroblastoma (5F31CA232468-03). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9949672. Licensed CC0.

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