Signature Genes Predict T-Cell Expansion in Cancer Immunotherapy

Modern cancer immunotherapies rely on the ability of CD8⁺ T cells to rapidly multiply within tumors, generating the immune force needed to eliminate cancer cells. However, the biological triggers behind this burst of T cell proliferation have remained elusive—limiting doctors’ ability to predict which patients will respond to treatment. Now, scientists have identified a unique genetic signature that predicts and can potentially reactivate this expansion process, opening a path to more precise and effective immunotherapies.

An international research team, led by the Tokyo University of Science (Tokyo, Japan;), has developed a new longitudinal approach to monitor how T cells evolve inside tumors over time. Their findings, published in Nature Communications, provide the first comprehensive view of how immune cells dynamically expand during cancer treatment and how this activity can be therapeutically restored.

Image: The research provides the first detailed view of how immune cells expand during cancer treatment and how this process can be restored (Photo courtesy of Shutterstock)

To achieve this, the researchers created a multi-site tumor model in mice, implanting tumors in different locations to enable sequential sampling of T cells across time. By leveraging unique T cell receptor (TCR) sequences as natural barcodes, they tracked hundreds of individual CD8⁺ T cell clones as they expanded or contracted, creating a clonal-level map of immune activity previously unattainable in cancer research.

Using single-cell RNA and TCR sequencing, the team discovered a distinct gene set—dubbed the “expansion signature”—that appeared in T cells just before they began to multiply. This gene signature strongly predicted which cells would proliferate in both untreated and immunotherapy-treated mice.

The predictive power held across several major immunotherapy types, including programmed cell death-ligand 1 (PD-L1), cytotoxic T-lymphocyte associated protein 4 (CTLA-4), and lymphocyte activation gene-3 (LAG-3) checkpoint inhibitors. In human patients receiving immunotherapies such as programmed cell death protein 1 (PD-1) blockade or chimeric antigen receptor (CAR)-T cell therapy, high expression of the expansion signature correlated with improved survival outcomes.

Even after T cells began to contract, a subset retained the potential to reignite proliferation. When the researchers applied LAG-3 blockade therapy, these dormant cells reactivated, triggering a renewed burst of T cell expansion and restoring anti-tumor activity. This demonstrates that the expansion signature could not only serve as a predictive biomarker but also as a therapeutic target for reawakening exhausted immune responses.

“Our work opens the door to a dynamic understanding of how immunotherapies succeed or fail in real time,” said TUS Associate Professor Satoshi 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.”

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Tokyo University of Science