Intratumoral expression levels of <i>PD-L1</i>, <i>GZMA</i>, and <i>HLA-A</i> along 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 the <i>PD-L1</i> (<i>p</i> = 0.03), expression levels of PD-1 ligand-2 (<i>PD-L2</i>), granzyme A (<i>GZMA</i>) and human leukocyte antigen-A (<i>HLA-A</i>) in the pre-treatment tumors were significantly higher (<i>p</i> = 0.04, <i>p</i> = 0.01 and <i>p</i> = 0.006, respectively) in responders (n = 5) than in non-responders (n = 8). With nivolumab treatment, tumors in responders exhibited a substantial increase of <i>CD8</i>, <i>GZMA</i> and perforin 1 (<i>PRF1</i>) expression levels as well as increased ratio of <i>TBX21/GATA3</i>, 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 (<i>PD-L1</i> and <i>PD-L2), GZMA</i> and <i>HLA-A</i> expression may respond preferentially to nivolumab treatment, which can enhance Th1-skewed cellular immunity with oligoclonal expansion of TILs.