Prospective development and validation of a liquid immune profile-based signature (LIPS) to predict response of patients with recurrent/metastatic cancer to immune checkpoint inhibitors

Abstract

BackgroundThe predictive power of novel biological markers for treatment response to immune checkpoint inhibitors (ICI) is still not satisfactory for the majority of patients with cancer. One should identify valid predictive markers in the peripheral blood, as this is easily available before and during treatment. The current interim analysis of patients of the ST-ICI cohort therefore focuses on the development and validation of a liquid immune profile-based signature (LIPS) to predict response of patients with metastatic cancer to ICI targeting the programmed cell death protein 1 (PD-1)/programmed cell death-ligand 1 (PD-L1) axis.MethodsA total of 104 patients were prospectively enrolled. 54 immune cell subsets were prospectively analyzed in patients’ peripheral blood by multicolor flow cytometry before treatment with ICI (pre-ICI; n=89), and after the first application of ICI (n=65). Pre-ICI, patients were randomly allocated to a training (n=56) and a validation cohort (n=33). Univariate Cox proportional hazards regression analysis and least absolute shrinkage and selection operator Cox model were used to create a predictive immune signature, which was also checked after the first ICI, to consider the dynamics of changes in the immune status.ResultsWhole blood samples were provided by 89 patients pre-ICI and by 65 patients after the first ICI. We identified a LIPS which is based on five immune cell subtypes: CD14high monocytes, CD8+/PD-1+ T cells, plasmacytoid dendritic cells, neutrophils, and CD3+/CD56+/CD16+ natural killer (NK)T cells. The signature achieved a high accuracy (C-index 0.74 vs 0.71) for predicting overall survival (OS) benefit in both the training and the validation cohort. In both cohorts, the low-risk group had significantly longer OS than the high-risk group (HR 0.26, 95% CI 0.12 to 0.56, p=0.00025; HR 0.30, 95% CI 0.10 to 0.91, p=0.024, respectively). Regarding the whole cohort, LIPS also predicted progression-free survival (PFS). The identified LIPS was not affected by clinicopathological features with the exception of brain metastases. NKT cells and neutrophils of the LIPS can be used as dynamic predictive biomarkers for OS and PFS after first administration of the ICI.ConclusionOur study identified a predictive LIPS for survival of patients with cancer treated with PD-1/PD-L1 ICI, which is based on immune cell subsets in the peripheral whole blood.Trial registration numberNCT03453892.

Association of Dynamic Changes in Peripheral Blood Indexes With Response to PD-1 Inhibitor-Based Combination Therapy and Survival Among Patients With Advanced Non-Small Cell Lung Cancer

“…Tumor-associated neutrophils have diametrically opposite effects at different molecular levels, which can be divided as anti-tumor N1 type and tumorpromoting N2 type (19)(20)(21). A prospective study with 104 patients identified a predictive immune signature (LIPS) based on the peripheral blood immunophenotype, including CD14 high monocytes, CD8 + /PD-1 + T cells, plasmacytoid dendritic cells, neutrophils, and CD3 + /CD56 + /CD16 + natural killer T cells (22). Based on LIPS, patients were categorized into low-and high-risk groups, and both PFS and OS were significantly longer for patients in the low-risk group than in the high-risk group, regardless of PD-L1 expression.…”

Hypofractionated Radiotherapy Upregulates Several Immune Checkpoint Molecules in Head and Neck Squamous Cell Carcinoma Cells Independently of the HPV Status While ICOS-L Is Upregulated Only on HPV-Positive Cells

“…In order to identify/select patients who are likely to respond positively to therapy with immune checkpoint inhibitors, research has moved specifically towards prognostic biomarkers in recent years [23]. We just recently identified a liquid immune profile-based signature to predict response of patients with recurrent/metastatic solid cancer to immune checkpoint inhibitors [24]. Furthermore, the limited response could be partly due to additional upregulation of other immune-suppressive immune checkpoint molecules on HNSCCs, as has already been demonstrated for the herpesvirus entry mediator (HVEM) in breast cancer [25].…”

Development of Exhaustion and Acquisition of Regulatory Function by Infiltrating CD8+CD28− T Lymphocytes Dictate Clinical Outcome in Head and Neck Cancer

“…This finding sheds new light on CD8+ T cell exhaustion, interpreting this phenomenon not only as the loss of effector activities but also as a progressive functional switch from effector to regulatory functions. The recent finding that enrichment of peripheral CD8+PD1+ T cell associates with poor overall survival in a cohort of patients affected by metastatic cancer (≈50% HNSCC) and submitted to immune-checkpoint inhibitors [ 53 ] may be interpreted as a clinical consequence of the biologic phenomena highlighted by our data.…”