title: Intratumoral expression levels ofPD-L1,GZMA, andHLA-Aalong with oligoclonal T cell expansion associate with response to nivolumab in metastatic melanoma.
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 thePD-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 andp= 0.006, respectively) in responders (n = 5) than in non-responders (n = 8). With nivolumab treatment, tumors in responders exhibited a substantial increase ofCD8,GZMAand perforin 1 (PRF1) expression levels as well as increased ratio ofTBX21/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-L1andPD-L2), GZMAandHLA-Aexpression may respond preferentially to nivolumab treatment, which can enhance Th1-skewed cellular immunity with oligoclonal expansion of TILs.
authors.affiliation: Department of Medicine, The University of Chicago , Chicago, IL, USA.
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Inoue
authors.affiliation: Department of Medicine, The University of Chicago , Chicago, IL, USA.
authors.forename: Jae-Hyun
authors.initials: JH
authors.lastname: Park
authors.affiliation: Department of Medicine, The University of Chicago , Chicago, IL, USA.
authors.forename: Kazuma
authors.initials: K
authors.lastname: Kiyotani
authors.affiliation: Department of Medicine, The University of Chicago , Chicago, IL, USA.
authors.forename: Makda
authors.initials: M
authors.lastname: Zewde
authors.affiliation: Department of Dermatology and Plastic Surgery, Faculty of Life Sciences, Kumamoto University , Kumamoto, Japan.
authors.forename: Azusa
authors.initials: A
authors.lastname: Miyashita
authors.affiliation: Department of Dermatology and Plastic Surgery, Faculty of Life Sciences, Kumamoto University , Kumamoto, Japan.
authors.forename: Masatoshi
authors.initials: M
authors.lastname: Jinnin
authors.affiliation: Department of Dermatology, Shinshu University School of Medicine , Matsumoto, Japan.
authors.forename: Yukiko
authors.initials: Y
authors.lastname: Kiniwa
authors.affiliation: Department of Dermatology, Shinshu University School of Medicine , Matsumoto, Japan.
authors.forename: Ryuhei
authors.initials: R
authors.lastname: Okuyama
authors.affiliation: Department of Dermatology, Faculty of Medicine, The University of Tsukuba , Tsukuba, Japan.
authors.forename: Ryota
authors.initials: R
authors.lastname: Tanaka
authors.affiliation: Department of Dermatology, Faculty of Medicine, The University of Tsukuba , Tsukuba, Japan.
authors.forename: Yasuhiro
authors.initials: Y
authors.lastname: Fujisawa
authors.affiliation: Department of Geriatric and Environmental Dermatology, Nagoya City University, Graduate School of Medical Sciences , Nagoya, Japan.
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Kato
authors.affiliation: Department of Geriatric and Environmental Dermatology, Nagoya City University, Graduate School of Medical Sciences , Nagoya, Japan.
authors.forename: Akimichi
authors.initials: A
authors.lastname: Morita
authors.affiliation: Department of Dermatology, Kyoto Prefectural University of Medicine, Graduate School of Medical Science , Kyoto, Japan.
authors.forename: Jun
authors.initials: J
authors.lastname: Asai
authors.affiliation: Department of Dermatology, Kyoto Prefectural University of Medicine, Graduate School of Medical Science , Kyoto, Japan.
authors.forename: Norito
authors.initials: N
authors.lastname: Katoh
authors.affiliation: Department of Dermatology, Nagoya University Graduate School of Medicine , Nagoya, Japan.
authors.forename: Kenji
authors.initials: K
authors.lastname: Yokota
authors.affiliation: Department of Dermatology, Nagoya University Graduate School of Medicine , Nagoya, Japan.
authors.forename: Masashi
authors.initials: M
authors.lastname: Akiyama
authors.affiliation: Department of Dermatology and Plastic Surgery, Faculty of Life Sciences, Kumamoto University , Kumamoto, Japan.
authors.forename: Hironobu
authors.initials: H
authors.lastname: Ihn
authors.affiliation: Department of Dermatology and Plastic Surgery, Faculty of Life Sciences, Kumamoto University , Kumamoto, Japan.
authors.forename: Satoshi
authors.initials: S
authors.lastname: Fukushima
authors.affiliation: Department of Medicine, The University of Chicago , Chicago, IL, USA.
authors.forename: Yusuke
authors.initials: Y
authors.lastname: Nakamura
keywords: Metastatic melanoma; PD-1; T-cell receptor sequencing; nivolumab; oligoclonal T cell expansion