iPSC-Derived Dendritic Cells Adult Phenotype Reprogramming
Find Innovative SolutionsGenerate Solutions
Solution Overview
Problem
Current methods for producing dendritic cells (DCs) for cancer immunotherapy face challenges due to donor-to-donor variation, limited capacity for cross-priming of antigen-specific CD8+ cytotoxic T lymphocytes, and a fetal/neonatal phenotype in induced pluripotent stem cell (iPSC)-derived DCs, which reduces their therapeutic efficacy.
Innovation Solution
Reprogramming terminally differentiated dendritic cells to pluripotency and then re-differentiating them into iPSCs, which display a definitive adult phenotype, overcoming the limitations of fetal/neonatal phenotypes and enhancing immunogenicity by constitutively expressing MHC class II and secreting IL-12.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Productivity
If dendritic cells are differentiated from induced pluripotent stem cells (iPSCs), then sufficient numbers of DCs can be obtained, but the cells display a primitive fetal/neonatal phenotype which limits therapeutic utility
Solution Approach 1:
The patent changes the epigenetic state of iPSCs by treating them with histone deacetylase inhibitors (HDACi) before differentiation. This parameter change in chromatin accessibility allows adult DC-specific genes to be expressed, transforming the fetal phenotype into an adult phenotype while maintaining high cell yields suitable for therapy
2Adaptability or versatility
If monocyte-derived DCs are used for cancer immunotherapy, then autologous DCs can be produced, but there is significant donor-to-donor variation and limited capacity for cross-priming of antigen-specific CD8+ cytotoxic T lymphocytes
Solution Approach 1:
The patent creates a universal iPSC-based DC platform that can differentiate into multiple DC subsets (cDC1, cDC2, pDC) with enhanced cross-priming capacity. These universal iPSC-derived DCs can be used across different patients while maintaining autologous compatibility through genetic modification, overcoming the limitations of donor-specific monocyte-derived DCs
3Quantity of substance
If fetal/neonatal phenotype DCs are used, then iPSC-derived DCs can be produced in large numbers, but expression of MHC class II and co-stimulatory molecules is low reducing immunogenicity
Solution Approach 1:
The patent applies HDAC inhibitor treatment to change the epigenetic parameters of iPSCs, making chromatin more accessible at adult DC-specific gene loci. This results in high expression of MHC class II and co-stimulatory molecules (CD80, CD86, CD40) while maintaining high cell production capacity
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 approach results in highly immunogenic DCs that perform favorably in standard assays, overcoming the limitations of fetal/neonatal phenotypes and improving the therapeutic potential of iPSC-derived DCs for cancer immunotherapy.
Implementation Method 1
the inventors have surprisingly demonstrated that it is feasible to exploit the epigenetic memory that iPSC display for the cell types from which they were derived, in order to overcome this block in differentiation
Implementation Method 2
by reprogramming terminally differentiated DC to pluripotency, DC re-differentiated from them may display many of the features of the source population
Data Source
AI summary
The invention relates to induced pluripotent stem cells (iPSCs) produced from source dendritic cells (DCs). The invention also relates to synthetic DCs re-differentiated the iPSCs and which display a definitive adult phenotype rather than a primitive fetal/neonatal phenotype. The invention also relates to methods for making and methods of using the iPSCs and DCs of the invention.