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

ABSTRACT: OBJECTIVES:A 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 METHODS:Metastatic 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. RESULTS:30 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). CONCLUSION:This 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.

SUBMITTER: Hurkmans DP

PROVIDER: S-EPMC7183487 | biostudies-literature | 2020 May

REPOSITORIES: biostudies-literature

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

Hurkmans Daan P DP Kuipers Merian E ME Smit Jasper J van Marion Ronald R Mathijssen Ron H J RHJ Postmus Piet E PE Hiemstra Pieter S PS Aerts Joachim G J V JGJV von der Thüsen Jan H JH van der Burg Sjoerd H SH

Cancer immunology, immunotherapy : CII 20200212 5

<h4>Objectives</h4>A 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<sup>+</sup> T cell infiltration, HLA class-I and PD-L1 expression in the tumor.<h4>Materials and methods</h4>Metastatic NSCLC patients were prospectively included in an immune-monitoring trial (NTR7015) between April 2016-August 2017, retrospectively analyzed in F ...[more]

PMID: 32047958

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Project description:BACKGROUND:Brain metastases (Bmets) are frequent; however, limited data exist on the efficacy of immunotherapy in these lesions. The aims of the study were to analyze the immunohistochemical expressions of programmed death ligand 1 (PD-L1) and CD8 in Bmets and to compare them with their expressions in paired primary tumors, as well as correlate the results with clinicopathological features. METHODS:This is a retrospective study of 233 patients with Bmets and 111 paired primaries. Clinical, histological, and molecular data were recorded and compared with the immunohistochemical results of PD-L1 and CD8 expressions. The statistical analysis included ?2 test, Cramer's V test, factorial analyses of variance, simple regression analysis, and Kaplan-Meier analysis with log-rank product limit estimation. RESULTS:PD-L1 expression was found in 23.6% of Bmets and in 29.0% of primary tumors with concordant expression between them in 75.5% of cases. Bmets PD-L1 expression was associated with primary tumor PD-L1 expression and the primary tumor type. Significant CD8 peritumoral expression was found in 68.6% of Bmets and in 87.7% of primary tumors. CD8 expression was concordant between primary and metastatic tumors in 73.3% of cases. Bmets CD8 expression was associated with primary tumor CD8 expression and primary tumor type. PD-L1 expression was associated with CD8 expression in both primary and metastatic tumors. The concordance between primary and metastatic tumor PD-L1 expression was independent of all factors studied. The concordance between primary and metastatic CD8 expressions was marginally associated to the time of Bmets development. No prognostic role for PD-L1 and CD8 expression in Bmets was found. CONCLUSION:PD-L1 and CD8 Bmets expressions are associated with the primary tumor type and its PD-L1 and CD8 expressions. No factor predicts the discordance for PD-L1 expression, while time to Bmets development is associated with CD8 expression discordance.

Dataset Information

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

Publications

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

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