Signature genes that predict T-Cell expansion in cancer immunotherapy

New Delhi: The ability of CD8⁺ T cells, a type of immune cell, to rapidly proliferate inside tumors is key to the success of cancer immunotherapy. In a new study, scientists from Tokyo University of Science, Japan, have identified a set of ‘signature’ genes that can determine whether these immune cells will multiply or stall within the tumor. Their findings provide a powerful pan-immunotherapy biomarker for treatment monitoring and pave the way for next-generation immunodynamic therapies.

The ability of immune cells—particularly CD8⁺ T cells—to launch a rapid burst of proliferation inside tumors is key to the success of modern day cancer immunotherapies. However, the factors and mechanisms that drive this burst in proliferation remain poorly understood, making it difficult to predict which patients will benefit from treatment. A deeper understanding of this T cell burst could also guide the development of new therapies that enhance T cell proliferation and improve treatment outcomes.

To tackle this challenge, an international team of researchers led by Associate Professor Satoshi Ueha and Professor Kouji Matsushima from the Research Institute for Biomedical Sciences, Tokyo University of Science (TUS), Japan, developed a novel approach to monitor CD8⁺ T cell activity over time. Their findings, recently published in the journal Nature Communications on October 20, 2025, sheds new light on how T cells expand in the tumor—and how their expansion can be predicted, and ultimately, therapeutically reactivated.

“The development of immunotherapies has been hindered by our inability to comprehensively monitor their effects on immune cells—particularly cancer-fighting T cells—over time,” explains Dr. Ueha. “Building on our previous work, we developed a method to track these cells longitudinally in the tumor, allowing us to gain deeper insights into the burst of proliferation that drives effective anti-tumor responses.”

The researchers created a ‘multi-site tumor model’ in mice, implanting tumors at different anatomical locations to allow for sequential sampling of T cells over time. By using unique T cell receptor (TCR) sequences as natural barcodes, the team was able to track hundreds of individual CD8⁺ T cell clones as they expanded or contracted over a week—yielding a dynamic, clonal-level view of the immune response to cancer that had previously been out of reach.

Using next-generation single-cell RNA and TCR sequencing, the team discovered that expanding T cells consistently expressed a specific set of genes prior to proliferation. This coordinated gene set—called the “expansion signature”—could identify T cells that were primed for growth. The expansion signature proved to be a strong predictor of T cell expansion in both untreated and immunotherapy-treated mice, including those receiving programmed cell death-ligand protein 1 and cytotoxic T-lymphocyte associated protein 4 or lymphocyte activation gene-3 (LAG-3) checkpoint blockade therapy. Notably, its expression in human patients receiving various immunotherapies, including programmed cell death protein 1 blockade and chimeric antigen receptor-T cell therapy correlated with improved survival outcomes.

While the expression of expansion signature faded over time, prior to T cell contraction, the researchers found that a specific population of T cells with the potential to reignite expansion remained within the tumor. To test this, the team administered LAG-3 blockade and observed reactivation of the expansion signature along with renewed proliferation of previously contracted T cell clones. 

These findings position the expansion signature as a powerful pan-immunotherapy biomarker for tracking, predicting, and potentially reinvigorating the anti-tumor T cell response. “Our work opens the door to a dynamic understanding of how immunotherapies succeed or fail in real time,” says Dr. Ueha. “We hope that the expansion signature can serve not only as a predictor of treatment response but also as a guide for designing new therapies that can reawaken the immune system when it begins to falter. Ultimately, this could bring us closer to truly personalized immunotherapy.” The researchers hope that the expansion signature will ultimately pave the way for the development of new therapies that modulate immune cell dynamics. Tuning T cell proliferation provides a granular control of the immune response that could both maximize treatment efficacy and minimize the effect of adverse events .

In summary, this study captures the T cell expansion dynamics that are critical for the success of cancer immunotherapies. By uncovering the genetic signature that predicts and even helps reinvigorate T cell proliferation, the researchers provide a powerful pan-immunotherapy biomarker for treatment monitoring that opens the doors to the development of next-generation immunodynamic therapies.