The effect of metabolic programming on aGC/iNKT cell immunotherapy

• Grant number: 25/18881-0
• Support Opportunities: Scholarships in Brazil - Doctorate
• Start date: October 01, 2025
• End date: March 31, 2029
• Field of knowledge: Biological Sciences - Immunology - Cellular Immunology
• Principal Investigator: Alexandre de Castro Keller
• Grantee: Amanda Maria de Queiroz
• Host Institution: Escola Paulista de Medicina (EPM). Universidade Federal de São Paulo (UNIFESP). Campus São Paulo. São Paulo , SP, Brazil
• Associated research grant: 24/05664-9 - The plasticity of non-conventional lymphocytes in immunological responses: perspectives and alternatives, AP.TEM

Abstract

The antitumor efficiency of alpha-galactosylceramide (aGC)depends both on IFN-gamma production and on cytotoxic pathways such as FasL and NKG2D. Recent data from our group show that glucose metabolism is a critical process for IFN-gamma production by iNKT lymphocytes when stimulated with aGC. Therefore, it is reasonable to assume that in a glucose-deprived environment-commonly observed during tumor implantation and development-the antitumor activity of iNKT lymphocytes is impaired. In this context, we believe that in vitro metabolic reprogramming of iNKT lymphocytes, whether through pharmacological agents or gene editing (CRISPR-Cas9), followed by activation and adoptive transfer, represents an alternative strategy to overcome the impact of the microenvironment on the efficiency of their antitumor activity.Another point we intend to explore is the use of gene editing to redirect iNKT lymphocytes to the site of interest, thereby avoiding or mitigating the risk of adverse side effects. For example, the CXCR6 receptor confers to these cells the characteristic of patrolling sinusoidal vessels in the liver, where, upon activation, they promote tissue damage, while CCR4 is responsible for their migration to the pulmonary parenchyma. Therefore, in the case of lung metastasis, we should be able to direct iNKT lymphocytes to the target organ by manipulating CXCR6 expression, either through neutralizing antibodies or gene editing. It is worth noting that even in the absence of CXCR6, treatment with aGC is still capable of inhibiting tumor growth, further reinforcing the potential of this approach.