# Regenerative Immunotherapy for Cancer: Transcription Factor Reprogramming of Tumor-Specific T Cells

## TL;DR

This paper reviews how reprogramming exhausted T cells could improve cancer immunotherapy by restoring their stem-like properties and functionality.

## Contribution

The paper provides an overview of transcription factor reprogramming as a novel strategy to regenerate tumor-specific T cells for improved immunotherapy outcomes.

## Key findings

- T cell exhaustion limits immunotherapy effectiveness due to loss of stemness and effector functions.
- Transcription factor reprogramming offers a way to restore T cell functionality but faces challenges in efficiency and resource demands.
- Current protocols for T cell reprogramming and re-maturation are lengthy and costly, hindering clinical translation.

## Abstract

Immunotherapy has revolutionized cancer treatment. However, these strategies are contingent upon the quality of a patient’s pre-existing anti-tumor immune response, limiting the clinical efficacy. T cell exhaustion—a cellular program characterized by loss of stemness and anti-tumor effector functions—critically limits the quality of a patient’s tumor-specific T cell repertoire and thereby their likelihood of experiencing clinical benefit from immunotherapy. Transcription factor reprogramming of tumor-specific T cells (with subsequent maturation techniques) is envisioned as a strategy to restore stemness and functionality to a patient’s tumor-specific T cell repertoire and turn an immunotherapy non-responder into a responder. Unfortunately, current T cell reprogramming and re-maturation protocols require extended culture periods and are prohibitively resource-intensive. Herein, we discuss the state of these approaches alongside progress toward clinical application.

Cell-based immunotherapy is a promising treatment strategy for cancer. Particularly in the case of solid tumors, however, this strategy only benefits a minority of patients. A critical limitation to immunotherapy is T cell exhaustion, a terminal differentiation state characterized by loss of self-renewal and cytotoxic capacity. For over a decade, regenerative immunology approaches to overcome exhaustion and restore stem-like features of T cells have been pursued. The reprogramming of tumor-specific T cells back to a less-differentiated, stem-like state using induced pluripotent stem cell (iPSC) technology has been viewed as a powerful and highly appealing strategy to overcome the limitations imposed by exhaustion. However, clinical translation of these approaches has been stymied by the requirement for subsequent iPSC-to-T cell re-maturation strategies, vanishingly low efficiencies, and resource-intensive cell culture protocols. In this review, we discuss the emergence of transcription factor reprogramming to iPSCs, contemporary techniques for T cell reprogramming, as well as techniques for re-differentiation into mature T cells. We discuss the potential clinical utility of T cell reprogramming and re-maturation strategies alongside progress and major roadblocks toward clinical translation. If these challenges can be addressed, transcription factor reprogramming of T cells into iPSCs and subsequent re-maturation into tumor-specific stem-like T cells may represent an incredibly efficacious approach to cancer immunotherapy.