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

Hurkmans, D.P.; Kuipers, M.E.; Smit, J.; Marion, R. van; Mathijssen, R.H.J.; Postmus, P.E.; ... ; Burg, S.H. van der (2020)

Article / Letter to editor

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.

• Nivolumab
• NSCLC
• TMB
• Tumor microenvironment
• Biomarker

• All authors: Hurkmans, D.P.; Kuipers, M.E.; Smit, J.; Marion, R. van; Mathijssen, R.H.J.; Postmus, P.E.; Hiemstra, P.S.; Aerts, J.G.J.V.; Thusen, J.H. von der; Burg, S.H. van der
• Date: 2020-02-12
• Journal: Cancer Immunology, Immunotherapy
• Volume: 69
• Issue: 5
• Pages: 771 - 777
• DOI: doi:10.1007/s00262-020-02506-x
• Link: https://link.springer.com/article/10.1007/s00262-020-02506-x