Tumor mutational load, CD8+ T cells, expression of PD-L1 and HLA class I to guide immunotherapy decisions in NSCLC patients

Daan P Hurkmans,Ron H J Mathijssen,Joachim G J V Aerts,Piet E Postmus,Pieter S Hiemstra,Jasper Smit,Jan H Von Der Thüsen,Sjoerd H Van Der Burg,Merian E Kuipers,Ronald Van Marion

doi:10.1007/s00262-020-02506-x

Daan P Hurkmans, Ron H J Mathijssen + Show 8 more

Open Access

https://doi.org/10.1007/s00262-020-02506-x

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Abstract

ObjectivesA minority of NSCLC patients benefit from anti-PD1 immune checkpoint inhibitors. A rational combination of biomarkers is needed. The objective was to determine the predictive value of tumor mutational load (TML), CD8+ T cell infiltration, HLA class-I and PD-L1 expression in the tumor.Materials and methodsMetastatic NSCLC patients were prospectively included in an immune-monitoring trial (NTR7015) between April 2016-August 2017, retrospectively analyzed in FFPE tissue for TML (NGS: 409 cancer-related-genes) and by IHC staining to score PD-L1, CD8+ T cell infiltration, HLA class-I. PFS (RECISTv1.1) and OS were analyzed by Kaplan–Meier methodology.Results30 patients with adenocarcinoma (67%) or squamous cell carcinoma (33%) were included. High TML was associated with better PFS (p = 0.004) and OS (p = 0.025). Interaction analyses revealed that patients with both high TML and high total CD8+ T cell infiltrate (p = 0.023) or no loss of HLA class-I (p = 0.026), patients with high total CD8+ T cell infiltrate and no loss of HLA class-I (p = 0.041) or patients with both high PD-L1 and high TML (p = 0.003) or no loss of HLA class-I (p = 0.032) were significantly associated with better PFS. Unsupervised cluster analysis based on these markers revealed three sub-clusters, of which cluster-1A was overrepresented by patients with progressive disease (15 out of 16), with significant effect on PFS (p = 0.007).ConclusionThis proof-of-concept study suggests that a combination of PD-L1 expression, TML, CD8+ T cell infiltration and HLA class-I functions as a better predictive biomarker for response to anti-PD-1 immunotherapy. Consequently, refinement of this set of biomarkers and validation in a larger set of patients is warranted.

Highlights

Tumors evade T-cell mediated destruction by exploiting inhibitory immune checkpoints such as the progressive disease (PD)-1/ PD-L1 pathway
The expression patterns of HLA-A and HLA-B/C as well as the total C D8+ T cell infiltration in these patients were similar to what we reported before in a comparable group of NSCLC patients [10]
The present proof-of-concept study suggests that in addition to PD-L1 expression tumor mutational load (TML), CD8+ T cell infiltration and HLA class I expression are associated with PFS and predict the response to anti-PD-1 immunotherapy

Summary

Introduction

Tumors evade T-cell mediated destruction by exploiting inhibitory immune checkpoints such as the PD-1/ PD-L1 pathway. The efficacy of treatment with immune checkpoint inhibitors (ICIs) targeting this pathway in non–small-cell. The currently most widely used biomarker is PD-L1 expression in the tumor, as assessed by the PD-L1 tumor proportion score (TPS), which is positively associated with a response to ICI treatment in metastatic NSCLC patients [4]. The presence of tumor-infiltrating CD8+ T cells which recognize tumor antigens, when presented at the tumor cell surface in the context of HLA class I, is a prerequisite for successful ICI treatment. A strong C D8+ type 1 T cell infiltration of tumors critically contributes to a better clinical outcome in cancer, including NSCLC [6]. While TML is an emerging biomarker, CD8+ T cell infiltration and HLA expression have not been considered as predictive biomarkers in NSCLC

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