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S1P in Tumor Microenvironment and Modulation of Anti-Tumor-Directed T-Cell Responses
Patrícia A António1, Joana R Lérias1, Carolina M Gorgulho1
1Immunotherapy/ImmunoSurgery Laboratory, Cell Center at the Champalimaud Foundation, Avenida Brasília, 1400-038 Lisbon, Portugal.
Abstract:
Adoptive cell therapy (ACT) using tumor-infiltrating lymphocytes (TILs) has achieved clinically and biologically relevant responses in patients with solid cancer. Clinical efficacy has been increasingly linked to a specific T-cell phenotype, particularly CD8+ TILs exhibiting a progenitor stem-cell-like profile (CD39- CD69-). This review explores the critical role of the sphingosine-1-phosphate (S1P) axis in orchestrating these responses. We detail the biological antagonism between the activation marker CD69 and S1P receptor 1 (S1PR1), where mutual exclusivity dictates thymic selection, if T-cells are retained in tissues or allowed to recirculate and maintain long-term immune surveillance. The S1PR1:S1P axis is further recognized as a critical regulator of mitochondrial fitness, sustaining the high energetic demands of precursor T-cells. We examine the "double-edged sword" nature of S1P in the tumor microenvironment (TME), where it can drive pro-tumorigenic processes like angiogenesis and vascular mimicry (VM), be hijacked by cancer cells to create immune-excluded environments, or S1P can increase T-cell fitness. We summarize the current landscape of clinical trials (as of January 2026) that target S1P production or signaling to modulate anti-tumor responses or use S1P as a biologically relevant marker of treatment outcome.
Insights
Adoptive cell therapy (ACT) efficacy relies on specific T-cell phenotypes. The sphingosine-1-phosphate (S1P) axis critically influences T-cell function and anti-tumor responses in solid cancers.
Area of Science:
- Immunology
- Cancer Biology
- Pharmacology
Background:
- Adoptive cell therapy (ACT) with tumor-infiltrating lymphocytes (TILs) shows promise for solid cancers.
- Clinical success correlates with specific T-cell phenotypes, like CD8+ TILs with progenitor stem-cell-like profiles (CD39- CD69-).
Purpose of the Study:
- To review the role of the sphingosine-1-phosphate (S1P) axis in ACT and anti-tumor immunity.
- To explore S1P's dual function in the tumor microenvironment (TME) and its impact on T-cell fitness and tumor progression.
Main Methods:
- Literature review focusing on the S1P axis, T-cell phenotypes, and the TME.
- Analysis of biological antagonism between CD69 and S1P receptor 1 (S1PR1).
- Examination of S1P's role in mitochondrial fitness and T-cell energetics.
Main Results:
- The S1P axis, particularly S1PR1, is crucial for T-cell retention, recirculation, and immune surveillance.
- S1P acts as a double-edged sword in the TME, promoting angiogenesis and vascular mimicry while potentially enhancing T-cell fitness.
- Clinical trials are investigating S1P modulation for anti-tumor responses and using S1P as a treatment outcome marker.
Conclusions:
- The S1P axis is a key regulator of T-cell function and a critical factor in the efficacy of ACT for solid tumors.
- Targeting the S1P axis offers potential therapeutic strategies to enhance anti-tumor immunity and improve patient outcomes.
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