Overexpression of FOXO1 Enhances Memory Programming and Antitumor Potency of Chimeric Antigen Receptor (CAR) T Cells

Core Concepts

FOXO1 is a master regulator that promotes memory and restrains exhaustion in human CAR T cells, and its overexpression can enhance the antitumor activity of CAR T cells.

Abstract

The content discusses the importance of memory programming in chimeric antigen receptor (CAR) T cell therapies for cancer treatment. It highlights that the expression of memory-associated genes in CAR T cells is linked to their long-term persistence and clinical efficacy. The key findings are:

The transcription factor FOXO1 is responsible for promoting memory and restraining exhaustion in human CAR T cells. Inhibition or gene editing of FOXO1 diminished the expression of memory-associated genes, promoted an exhaustion-like phenotype, and impaired the antitumor activity of CAR T cells.

Overexpression of FOXO1 induced a gene-expression program consistent with T cell memory and increased chromatin accessibility at FOXO1-binding motifs. CAR T cells overexpressing FOXO1 retained their function, memory potential, and metabolic fitness in settings of chronic stimulation, and exhibited enhanced persistence and tumor control in vivo.

In contrast, overexpression of TCF1 (encoded by TCF7) did not enforce canonical memory programs or enhance the potency of CAR T cells.

FOXO1 activity correlated with positive clinical outcomes of patients treated with CAR T cells or tumor-infiltrating lymphocytes, underscoring the clinical relevance of FOXO1 in cancer immunotherapy.

The authors conclude that overexpressing FOXO1 can increase the antitumor activity of human CAR T cells, and highlight memory reprogramming as a broadly applicable approach for optimizing therapeutic T cell states.

Stats

The expression of memory-associated genes in CAR T cells is linked to their long-term persistence in patients and clinical efficacy.
Pharmacological inhibition or gene editing of endogenous FOXO1 diminished the expression of memory-associated genes, promoted an exhaustion-like phenotype and impaired the antitumour activity of CAR T cells.
CAR T cells that overexpressed FOXO1 retained their function, memory potential and metabolic fitness in settings of chronic stimulation, and exhibited enhanced persistence and tumour control in vivo.

Quotes

"FOXO1 is responsible for promoting memory and restraining exhaustion in human CAR T cells."
"Overexpression of FOXO1 induced a gene-expression program consistent with T cell memory and increased chromatin accessibility at FOXO1-binding motifs."
"FOXO1 activity correlated with positive clinical outcomes of patients treated with CAR T cells or tumour-infiltrating lymphocytes, underscoring the clinical relevance of FOXO1 in cancer immunotherapy."

Key Insights Distilled From

FOXO1 is a master regulator of memory programming in CAR T cells - Nature

by Alexander E.... at www.nature.com 04-10-2024

https://www.nature.com/articles/s41586-024-07300-8

Deeper Inquiries

What other transcription factors or epigenetic mechanisms may be involved in regulating memory programming in CAR T cells?

Memory programming in CAR T cells is a complex process involving various transcription factors and epigenetic mechanisms. Apart from FOXO1, other transcription factors such as TCF1, Eomes, and Bcl6 have been implicated in memory formation in T cells. TCF1, in particular, plays a crucial role in regulating stem-like memory T cells. Epigenetic mechanisms like DNA methylation, histone modifications, and chromatin accessibility also contribute to memory programming by controlling gene expression patterns. Understanding the interplay of these factors is essential for optimizing memory formation in CAR T cells.

How can the findings on FOXO1 overexpression be translated into more effective CAR T cell manufacturing and clinical protocols?

The findings on FOXO1 overexpression offer promising avenues for enhancing the efficacy of CAR T cell therapies. Translating these findings into clinical protocols involves strategies such as genetic engineering to overexpress FOXO1 in CAR T cells during manufacturing. This can be achieved through viral transduction or gene editing techniques like CRISPR-Cas9. Additionally, optimizing culture conditions to maintain FOXO1 activity and memory programming in CAR T cells can improve their persistence and antitumor activity in patients. Incorporating FOXO1 overexpression into existing manufacturing protocols can lead to the development of more potent and durable CAR T cell therapies.

What are the potential implications of memory programming in CAR T cells for other types of adoptive cell therapies, such as tumor-infiltrating lymphocytes or engineered T cell receptor therapies?

Memory programming in CAR T cells has significant implications for other adoptive cell therapies like tumor-infiltrating lymphocytes (TILs) and engineered T cell receptor (TCR) therapies. By understanding the key transcription factors and epigenetic mechanisms that drive memory formation in CAR T cells, similar strategies can be applied to enhance the memory phenotype in TILs or TCR-engineered T cells. This can improve the persistence, functionality, and long-term efficacy of these therapies in treating cancer. Memory programming may serve as a universal approach to optimize the therapeutic potential of various adoptive cell therapies, leading to better clinical outcomes for patients.