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

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. Ma...

Full description

Saved in:
Bibliographic Details
Published in:Cancer Immunology, Immunotherapy Immunotherapy, 2020-05, Vol.69 (5), p.771-777
Main Authors: Hurkmans, Daan P., Kuipers, Merian E., Smit, Jasper, van Marion, Ronald, Mathijssen, Ron H. J., Postmus, Piet E., Hiemstra, Pieter S., Aerts, Joachim G. J. V., von der Thüsen, Jan H., van der Burg, Sjoerd H.
Format: Article
Language:English
Subjects:
Adenocarcinoma
Aged
Antineoplastic Agents, Immunological - pharmacology
Antineoplastic Agents, Immunological - therapeutic use
B7-H1 Antigen - analysis
B7-H1 Antigen - antagonists & inhibitors
B7-H1 Antigen - immunology
B7-H1 Antigen - metabolism
Biomarkers
Biomarkers, Tumor - analysis
Biomarkers, Tumor - genetics
Biomarkers, Tumor - immunology
Biomarkers, Tumor - metabolism
Biopsy
Cancer Research
Carcinoma, Non-Small-Cell Lung - drug therapy
Carcinoma, Non-Small-Cell Lung - genetics
Carcinoma, Non-Small-Cell Lung - immunology
Carcinoma, Non-Small-Cell Lung - mortality
CD8 antigen
CD8-Positive T-Lymphocytes - immunology
Clinical Decision-Making - methods
Cluster analysis
Disease Progression
Female
Follow-Up Studies
Histocompatibility antigen HLA
Histocompatibility Antigens Class I - analysis
Histocompatibility Antigens Class I - immunology
Histocompatibility Antigens Class I - metabolism
Humans
Immune checkpoint inhibitors
Immunology
Immunotherapy
Infiltration
Lung - pathology
Lung cancer
Lung Neoplasms - drug therapy
Lung Neoplasms - genetics
Lung Neoplasms - immunology
Lung Neoplasms - mortality
Lymphocytes
Lymphocytes T
Lymphocytes, Tumor-Infiltrating - immunology
Male
Medicine
Medicine & Public Health
Metastases
Middle Aged
Monoclonal antibodies
Mutation Rate
Nivolumab - pharmacology
Nivolumab - therapeutic use
Non-small cell lung carcinoma
Oncology
Original
Original Article
PD-1 protein
PD-L1 protein
Predictive Value of Tests
Progression-Free Survival
Proof of Concept Study
Prospective Studies
Response Evaluation Criteria in Solid Tumors
Retrospective Studies
Squamous cell carcinoma
Targeted cancer therapy
Citations: Items that this one cites
Items that cite this one
Online Access:Get full text
Tags: Add Tag
No Tags, Be the first to tag this record!
Description
Summary: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.
ISSN:0340-7004
1432-0851
DOI:10.1007/s00262-020-02506-x