Intratumoral expression levels of PD-L1, GZMA, and HLA-A along with oligoclonal T cell expansion associate with response to nivolumab in metastatic melanoma

被引：108

作者：

Inoue, Hiroyuki ^{[1
]}

Park, Jae-Hyun ^{[1
]}

Kiyotani, Kazuma ^{[1
]}

Zewde, Makda ^{[1
]}

Miyashita, Azusa ^{[2
]}

Jinnin, Masatoshi ^{[2
]}

Kiniwa, Yukiko ^{[3
]}

Okuyama, Ryuhei ^{[3
]}

Tanaka, Ryota ^{[4
]}

Fujisawa, Yasuhiro ^{[4
]}

Kato, Hiroshi ^{[5
]}

Morita, Akimichi ^{[5
]}

Asai, Jun ^{[6
]}

Katoh, Norito ^{[6
]}

Yokota, Kenji ^{[7
]}

Akiyama, Masashi ^{[7
]}

Ihn, Hironobu ^{[2
]}

Fukushima, Satoshi ^{[2
]}

Nakamura, Yusuke ^{[1
]}

机构：

[1] Univ Chicago, Dept Med, 5841 S Maryland Ave, Chicago, IL 60637 USA

[2] Kumamoto Univ, Dept Dermatol & Plast Surg, Fac Life Sci, Kumamoto, Japan

[3] Shinshu Univ, Dept Dermatol, Sch Med, Matsumoto, Nagano, Japan

[4] Univ Tsukuba, Dept Dermatol, Fac Med, Tsukuba, Ibaraki, Japan

[5] Nagoya City Univ, Grad Sch Med Sci, Dept Geriatr & Environm Dermatol, Nagoya, Aichi, Japan

[6] Kyoto Prefectural Univ Med, Grad Sch Med Sci, Dept Dermatol, Kyoto, Japan

[7] Nagoya Univ, Grad Sch Med, Dept Dermatol, Nagoya, Aichi, Japan

来源：

ONCOIMMUNOLOGY | 2016年 / 5卷 / 09期

关键词：

Metastatic melanoma; nivolumab; oligoclonal T cell expansion; PD-1; T-cell receptor sequencing; TUMOR-INFILTRATING LYMPHOCYTES; ANTI-PD-L1; ANTIBODY; CANCER; REPERTOIRE; BLOCKADE; IMMUNOTHERAPY; LIGANDS; SAFETY;

D O I：

10.1080/2162402X.2016.1204507

中图分类号：

R73 [肿瘤学];

学科分类号：

100214 ;

摘要：

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 (TCR-) 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.

引用

页数：7

共 31 条

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Wickrema, A. ;

Artz, A. ;

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Bishop, M. R. ;

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BONE MARROW TRANSPLANTATION, 2015, 50 (09) :1227-1234

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