ISG+ Dendritic Cells Cross-Dressing Anti-Tumor Immunity
Find Innovative SolutionsGenerate Solutions
Solution Overview
Problem
Current cancer therapies, such as checkpoint blockade therapy, rely on T cell infiltration but struggle to maintain highly functional T cells within the tumor microenvironment, with dysfunctional T cells promoting tumor escape, and the identities and phenotypes of stimulatory dendritic cells that induce and maintain these responses remain poorly understood.
Innovation Solution
Identification and characterization of a novel class of interferon-stimulated gene signature dendritic cells (ISG+ DCs) that present tumor antigens via 'cross-dressing' without internalization, activated by sensing tumor-derived double-stranded RNA, which can be harnessed to enhance anti-tumor responses.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If checkpoint blockade therapy is used to reinvigorate dysfunctional T cells, then anti-tumor immune response is enhanced, but the sustained presence of highly functional T cells in the tumor microenvironment cannot be maintained
Solution Approach 1:
The patent introduces ISG+ dendritic cells as intermediary cells that bridge the gap between checkpoint blockade therapy and sustained T cell function. These DCs express interferon-stimulated genes and present tumor antigens via cross-dressing, thereby maintaining T cell activation and functionality within the tumor microenvironment over time, resolving the contradiction between initial immune reinvigoration and sustained functional presence
Solution Approach 2:
The patent employs preliminary action by pre-activating dendritic cells with interferon stimulation before they encounter tumor antigens. This preliminary activation of ISG+ DCs prepares them to effectively present tumor antigens and sustain T cell responses, ensuring that functional T cells are maintained in the tumor microenvironment rather than becoming dysfunctional after initial activation
2Reliability
If T cell infiltration is increased in tumors, then sensitivity to checkpoint blockade therapy improves, but dysfunctional T cells promote tumor escape
Solution Approach 1:
The patent applies local quality by creating distinct functional zones within the tumor microenvironment. ISG+ dendritic cells establish localized areas of effective antigen presentation and T cell activation, ensuring that T cells in specific regions maintain high functionality rather than becoming uniformly dysfunctional, thereby preventing tumor escape while preserving therapeutic response
Solution Approach 2:
The patent changes the functional parameters of dendritic cells by inducing interferon-stimulated gene expression. This parameter change transforms ordinary DCs into ISG+ DCs with enhanced antigen presentation capacity via cross-dressing, thereby improving T cell functionality and preventing tumor escape mechanisms while maintaining sensitivity to checkpoint blockade therapy
3Reliability
If dendritic cell numbers or function are boosted to enhance checkpoint blockade responses, then dysfunctional T cell reactivation occurs, but the identities and phenotypes of stimulatory dendritic cells remain elusive
Solution Approach 1:
The patent uses molecular 'color coding' through interferon-stimulated gene expression signatures to identify ISG+ dendritic cells. These cells exhibit distinct gene expression profiles (upregulation of ISGs like IFIT1, MX1, OAS1) that serve as detectable markers, enabling researchers to identify and study the specific phenotype of stimulatory DCs that were previously elusive, while confirming their role in T cell reactivation
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 presence of ISG+ DCs correlates with tumor regression and can be used to induce a robust anti-tumor response, providing a prognostic indicator and therapeutic target for boosting anti-tumor immunity by enhancing their activity and numbers in tumors.
Implementation Method 1
these cells present tumor antigen in the context of MHC Class I in a manner that does not require internalization and digestion of tumor cells and/or antigens, as would be expected to occur in classical antigen cross-presentation. Instead, these cells present tumor antigen in the context of MHC Class I in a manner referred to herein as 'cross-dressing'
Implementation Method 2
Cross-dressing ISG+ DC are activated by sensing tumor-derived double-stranded RNA (dsRNA)
Data Source
AI summary
Provided herein are compositions and methods of use relating to a novel class of dendritic cells, referred to herein as ISG+ DC, having anti-tumor activity.