Metabolic Reprogramming of T Cells via Glycolytic Enzyme Overexpression
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Solution Overview
Problem
There is a need to enhance T cell-mediated immunity to tumors and improve T cell-based immunotherapies for cancer patients, as tumors manipulate the tumor microenvironment to impair T cell function and nutrient availability.
Innovation Solution
Genetically engineered hematopoietic cells, specifically T cells, are modified to express nucleic acid sequences encoding molecules involved in metabolic pathways such as glycolysis, including Hexokinase-2 (HK2), Phosphofructokinase (PFK), and Pyruvate Kinase (PKM), as well as glucose transporters like GLUT3, to enhance their metabolic capacity and function.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If T cells are used for cancer treatment, then antitumor activity is achieved, but T cell function is impaired due to tumor manipulation of the microenvironment
Solution Approach 1:
The patent modifies T cell metabolic parameters by introducing and overexpressing specific enzymes (Hexokinase-2, Phosphofructokinase, Pyruvate Kinase) and glucose transporters (GLUT3). These parameter changes enable T cells to alter their metabolic profile, increasing glycolytic flux and ATP production, thereby maintaining function despite the harmful tumor microenvironment conditions.
2Power
If T cells are engineered to express metabolic enzymes, then metabolic capacity and ATP production are enhanced, but device complexity increases
Solution Approach 1:
The patent combines multiple metabolic enzymes and glucose transporters into a single T cell population through genetic engineering. By merging the expression of Hexokinase-2, Phosphofructokinase, Pyruvate Kinase, and GLUT3 transporters, the invention creates a synergistic metabolic reprogramming effect that enhances ATP production without requiring separate complex systems for each function.
3Use of energy by moving object
If glucose uptake is increased to enhance energy metabolism, then ATP production improves, but glucose may be depleted in the tumor microenvironment
Solution Approach 1:
The patent introduces GLUT3 glucose transporters into T cells, effectively copying the high-affinity glucose uptake mechanism found in tumor cells. This allows T cells to efficiently capture glucose from the tumor microenvironment through receptor-mediated transport, enabling enhanced energy metabolism while the tumor's own glucose consumption creates a competitive but controlled glucose depletion dynamic.
Applied Scientific Principles
This section explains which scientific principles are used to turn an abstract innovation direction into a practical engineering solution.
Function Achieved in This Case
The genetically modified T cells exhibit improved cytokine secretion, increased glucose uptake, enhanced ATP production, and prolonged survival, leading to improved antitumor activity and therapeutic efficacy in cancer treatment.
Implementation Method 1
In glycolysis, glucose (C6H12O6) is converted into pyruvic acid (CH3COCO2H) and the free energy released in this process is used to form the high-energy molecules adenosine triphosphate (ATP) and reduced nicotinamide adenine dinucleotide (NADH)
Implementation Method 2
The transport of glucose across the plasma membrane into the cytosol is a rate-limiting step in glucose metabolism and is mediated by a family of glucose transporters (GLUTs)
Implementation Method 3
In each step of the glycolysis, important enzymes catalyze reactions. The main reactions in the glycolysis pathway are catalyzed by hexokinase, phosphofructokinase, and pyruvate kinase; hence, these enzymes have a regulatory role
Data Source
AI summary
The present disclosure relates to genetically engineered hematopoietic cell/s, specifically, lymphocytes, and more specifically, cells of the T cell lineage or a cell population comprising at least one of the cell/s. The disclosed cells comprises and/or expresses at least one nucleic acid sequence encoding at least one molecule involved directly or indirectly in at least one metabolic pathway. The present disclosure provides compositions, methods and uses of the engineered cells.