The Predictive and Prognostic Value of T- and B-cell Transcriptomic Signatures for Clinical Response to Immune Checkpoint Blockade in Pleural Mesothelioma
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Background
Malignant pleural mesothelioma (PM) is an aggressive cancer with limited treatment options. Although immune checkpoint blockade (ICB) with nivolumab plus ipilimumab improves overall survival and has become standard-of-care, responses are variable and there are no predictive biomarkers for treatment outcome among PM patients with epithelioid histology.
Methods
We developed an eight-gene T-cell and six-gene B-cell transcriptomic signature. To quantify T- and B-cell infiltration, a geometric-mean T- and B-cell expression score was calculated for each patient. Immune profiles were generated in three ICB-naïve PM cohorts (n = 448), and Kaplan-Meier analysis was used to evaluate prognostic value of the signatures. Predictive value was tested in five independent ICB-treated cohorts (n = 104).
Results
In ICB-naïve patients, high B-cell infiltration was associated with longer overall survival (hazard ratio (HR): 0.50, 95% confidence interval (CI): 0.31-0.82), whereas T-cell infiltration had no prognostic value. Among patients treated with 2 nd line treatment with nivolumab plus ipilimumab, high T-cell infiltration predicted better objective response and improved overall survival (HR: 0.06, 95% CI: 0.01-0.36). This effect was absent in patients treated with 2 nd line nivolumab alone or any other anti-PD1/PDL1 drug combined with non-immunotherapeutics. B-cell infiltration showed no predictive value in any ICB-treated group.
Conclusions
The eight-gene T-cell signature is a specific predictor of outcome after 2 nd line treatment with nivolumab plus ipilimumab, while B-cell infiltration is prognostic in ICB-naïve disease.
