Related Experiment Video
Updated: Sep 4, 2025
Analysis of Human T Cell Activity in an Allogeneic Co-Culture Setting of Pre-Treated Tumor Cells
Published on: March 7, 2025
Circulating L-arginine predicts the survival of cancer patients treated with immune checkpoint inhibitors
F Peyraud1, J-P Guégan2, D Bodet2
1Drug Development Department (DITEP), Gustave Roussy, Villejuif, France; Department of Medicine, Institut Bergonié, Bordeaux, France; Explicyte Immuno-Oncology, Bordeaux, France; University of Bordeaux, Bordeaux, France.
Background:
The discovery of immune checkpoint inhibitors (ICIs) has revolutionized the systemic approach to cancer treatment. Most patients receiving ICIs, however, do not derive benefits. Therefore, it is crucial to identify reliable predictive biomarkers of response to ICIs. One important pathway in regulating immune cell reactivity is L-arginine (ARG) metabolism, essential to T-cell activation. We therefore aimed to evaluate the association between baseline plasma ARG levels and the clinical benefit of ICIs.
Patients And Methods:
The correlation between ARG levels and clinical ICI activity was assessed by analyzing plasma samples obtained before treatment onset in two independent cohorts of patients with advanced cancer included in two institutional molecular profiling programs (BIP, NCT02534649, n = 77; PREMIS, NCT03984318, n = 296) and from patients in a phase 1 first-in-human study of budigalimab monotherapy (NCT03000257). Additionally, the correlation between ARG levels and ICI efficacy in preclinical settings was evaluated using a syngeneic mouse model of colorectal cancer responsive to ICIs. Using matched peripheral blood mononuclear cell (PBMC) plasma samples, we analyzed the correlation between ARG levels and PBMC features through multiplexed flow cytometry analysis.
Results:
In both discovery and validation cohorts, low ARG levels at baseline (<42 μM) were significantly and independently associated with a worse clinical benefit rate, progression-free survival, and overall survival. Moreover, at the preclinical level, the tumor rejection rate was significantly higher in mice with high baseline ARG levels than in those with low ARG levels (85.7% versus 23.8%; P = 0.004). Finally, PBMC immunophenotyping showed that low ARG levels were significantly associated with increased programmed death-ligand 1 expression in several immune cell subsets from the myeloid lineage.
Conclusions:
We demonstrate that baseline ARG levels predict ICI response. Plasma ARG quantification may therefore represent an attractive biomarker to tailor novel therapeutic regimens targeting the ARG pathway in combination with ICIs.
Insights
Low L-arginine (ARG) levels predict poor response to immune checkpoint inhibitors (ICIs). Measuring ARG may help personalize cancer therapy by identifying patients who will benefit from ICIs or combination treatments.
Area of Science:
- Immunology
- Oncology
- Metabolomics
Background:
- Immune checkpoint inhibitors (ICIs) have transformed cancer treatment.
- However, many patients do not respond to ICIs, necessitating predictive biomarkers.
- L-arginine (ARG) metabolism is crucial for T-cell function and immune response.
Purpose of the Study:
- To investigate the association between baseline plasma L-arginine (ARG) levels and clinical benefit from ICIs.
- To explore ARG levels as a predictive biomarker for ICI response in cancer patients.
Main Methods:
- Analysis of plasma ARG levels in two independent patient cohorts and a phase 1 clinical trial.
- Evaluation of ARG levels in a preclinical mouse model of colorectal cancer.
- Correlation of ARG levels with peripheral blood mononuclear cell (PBMC) immunophenotypes using flow cytometry.
Main Results:
- Low baseline ARG levels (<42 μM) were significantly associated with worse clinical benefit, progression-free survival, and overall survival.
- Preclinical models showed higher tumor rejection rates in mice with high ARG levels.
- Low ARG levels correlated with increased PD-L1 expression on myeloid immune cells.
Conclusions:
- Baseline plasma ARG levels can predict response to immune checkpoint inhibitors.
- ARG quantification is a potential biomarker for tailoring cancer therapy, including combination strategies with ICIs.
