Peripheral Blood TCRβ Repertoire, IL15, IL2 and Soluble Ligands for NKG2D Activating Receptor Predict Efficacy of
Andrea Sesma1,2, Julian Pardo2,3,4, Dolores Isla1,2
1Medical Oncology Department, University Hospital Lozano Blesa, 50009 Zaragoza, Spain.
Abstract:
The development of immune checkpoint inhibitors (ICIs) has changed the therapeutic paradigm of lung cancer (LC), becoming the standard of treatment for previously untreated advanced non-small cell lung cancer (NSCLC) without actionable mutations. It has allowed the achievement of durable responses and resulted in significant survival benefits. However, not all patients respond; hence, molecular biomarkers are needed to help us predict which patients will respond. With this objective, a prospective observational study was designed, including a cohort of 55 patients with NSCLC who received ICIs. We studied whether biomarkers such as TCRβ and specific cytokines involved in the regulation of T cell activity were related to the immunotherapy response. In the survival analysis, it was found that patients with higher TCRβ clonality, lower TCRβ evenness, higher TCRβ Shannon diversity and lower TCRβ convergence had higher overall survival (OS) and progression-free survival (PFS). However, no statistically significant association was observed. Regarding cytokines, those patients with higher levels of IL-2 and IL-15 presented statistically significantly shorter OS and PFS, respectively. In fact, in the multivariable analysis, the high IL-15 level increased the risk of death by three times. Although the sample size was small and more studies are needed to confirm our results, our study reveals promising markers of responses to ICIs.
Insights
Predicting response to immune checkpoint inhibitors (ICIs) in lung cancer is crucial. This study found that while T cell receptor beta (TCRβ) diversity markers were not significant, higher IL-2 and IL-15 levels were associated with shorter survival in lung cancer patients.
Area of Science:
- Oncology
- Immunology
- Biomarker Research
Background:
- Immune checkpoint inhibitors (ICIs) are standard treatment for advanced non-small cell lung cancer (NSCLC) without actionable mutations, offering durable responses and survival benefits.
- However, predicting patient response to ICIs remains a challenge, necessitating the identification of reliable molecular biomarkers.
- T cell receptor beta (TCRβ) and cytokine profiles are potential indicators of immunotherapy response.
Purpose of the Study:
- To investigate the association between TCRβ repertoire characteristics and specific cytokines with treatment response in NSCLC patients receiving ICIs.
- To identify potential biomarkers for predicting overall survival (OS) and progression-free survival (PFS) in lung cancer patients undergoing immunotherapy.
Main Methods:
- A prospective observational study included 55 NSCLC patients treated with ICIs.
- Analysis of TCRβ repertoire metrics (clonality, evenness, diversity, convergence) and serum cytokine levels (IL-2, IL-15).
- Survival analysis (OS and PFS) correlated with biomarker data, including multivariable analysis.
Main Results:
- No statistically significant association was found between TCRβ repertoire metrics and survival outcomes (OS/PFS).
- Higher levels of Interleukin-2 (IL-2) were significantly associated with shorter OS.
- Elevated Interleukin-15 (IL-15) levels were significantly associated with shorter PFS, and multivariable analysis indicated a threefold increased risk of death.
Conclusions:
- While TCRβ repertoire metrics did not show predictive value in this cohort, specific cytokines like IL-2 and IL-15 may serve as potential negative biomarkers for ICI response in NSCLC.
- Higher IL-15 levels are a significant risk factor for mortality in NSCLC patients treated with ICIs.
- Further research with larger sample sizes is required to validate these findings and their clinical utility in predicting immunotherapy outcomes.
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