Intratumoral expression levels of PD-L1, GZMA, and HLA-A along with oligoclonal T cell expansion associate with response to nivolumab in metastatic melanoma. (1st September 2016)

• Record Type: Journal Article
• Authors: Inoue, Hiroyuki; Park, Jae-Hyun; Kiyotani, Kazuma; Zewde, Makda; Miyashita, Azusa; Jinnin, Masatoshi; Kiniwa, Yukiko; Okuyama, Ryuhei; Tanaka, Ryota; Fujisawa, Yasuhiro; Kato, Hiroshi; Morita, Akimichi; Asai, Jun; Katoh, Norito; Yokota, Kenji; Akiyama, Masashi; Ihn, Hironobu; Fukushima, Satoshi; Nakamura, Yusuke
• Is Part Of: Oncoimmunology. Volume 5:Number 9(2016)
• Publication Date: 2016-09-01
• Subjects: Metastatic melanoma -- nivolumab -- oligoclonal T cell expansion -- PD-1 -- T-cell receptor sequencing; Tumors -- Immunological aspects -- Periodicals; Neoplasms -- therapy -- Periodicals; Immunotherapy -- Periodicals; 616.994
• DOI: 10.1080/2162402X.2016.1204507
• Languages: English
• ISSNs: 2162-402X

Abstract

ABSTRACT: Immune checkpoint inhibitors blocking the interaction between programmed death-1 (PD-1) and PD-1 ligand-1 (PD-L1) are revolutionizing the cancer immunotherapies with durable clinical responses. Although high expression of PD-L1 in tumor tissues has been implicated to correlate with the better response to the anti-PD-1 therapies, this association has been controversial. In this study, to characterize immune microenvironment in tumors, we examined mRNA levels of immune-related genes and characterized T cell repertoire in the tumors of 13 melanoma patients before and after nivolumab treatment. We found that, in addition to the PD-L1 ( p = 0.03), expression levels of PD-1 ligand-2 ( PD-L2 ), granzyme A ( GZMA ) and human leukocyte antigen-A ( HLA-A ) in the pre-treatment tumors were significantly higher ( p = 0.04, p = 0.01 and p = 0.006, respectively) in responders (n = 5) than in non-responders (n = 8). With nivolumab treatment, tumors in responders exhibited a substantial increase of CD8, GZMA and perforin 1 ( PRF1 ) expression levels as well as increased ratio of TBX21/GATA3, suggesting dominancy of helper T cell type 1 (Th1) response to type 2 (Th2) response. T cell receptor β (TCR-β) repertoire analysis revealed oligoclonal expansion of tumor-infiltrating T lymphocytes (TILs) in the tumor tissues of the responders. Our findings suggest that melanoma harboring high PD-1 ligands ( PD-L1 and PD-L2), GZMA and HLA-A expression may respond preferentially to nivolumab treatment, which can enhance Th1-skewed cellular immunity with oligoclonal expansion of TILs.