Abstract
<div>Abstract<p><b>Purpose:</b> Blocking the immunosuppressive PD-1/PD-L1 pathway has antitumor activity in multiple cancer types, and PD-L1 expression on tumor cells and infiltrating myeloid cells correlates with the likelihood of response. We previously found that <i>IFNG</i> (interferon-gamma) was overexpressed by tumor-infiltrating lymphocytes in PD-L1<sup>+</sup> versus PD-L1(−) melanomas, creating adaptive immune resistance by promoting PD-L1 display. This study was undertaken to identify additional factors in the PD-L1<sup>+</sup> melanoma microenvironment coordinately contributing to immunosuppression.</p><p><b>Experimental Design:</b> Archived, formalin-fixed paraffin-embedded melanoma specimens were assessed for PD-L1 protein expression at the tumor cell surface with IHC. Whole-genome expression analysis, quantitative (q)RT-PCR, IHC, and functional <i>in vitro</i> validation studies were used to assess factors differentially expressed in PD-L1<sup>+</sup> versus PD-L1(−) melanomas.</p><p><b>Results:</b> Functional annotation clustering based on whole-genome expression profiling revealed pathways upregulated in PD-L1<sup>+</sup> melanomas, involving immune cell activation, inflammation, and antigen processing and presentation. Analysis by qRT-PCR demonstrated overexpression of functionally related genes in PD-L1<sup>+</sup> melanomas, involved in CD8<sup>+</sup> T-cell activation (<i>CD8A</i>, <i>IFNG</i>, <i>PRF1</i>, and <i>CCL5</i>), antigen presentation (<i>CD163</i>, <i>TLR3</i>, <i>CXCL1</i>, and <i>LYZ</i>), and immunosuppression [<i>PDCD1</i> (PD-1), <i>CD274</i> (PD-L1), and <i>LAG3</i>, <i>IL10</i>]. Functional studies demonstrated that some factors, including IL10 and IL32-gamma, induced PD-L1 expression on monocytes but not tumor cells.</p><p><b>Conclusions:</b> These studies elucidate the complexity of immune checkpoint regulation in the tumor microenvironment, identifying multiple factors likely contributing to coordinated immunosuppression. These factors may provide tumor escape mechanisms from anti–PD-1/PD-L1 therapy, and should be considered for cotargeting in combinatorial immunomodulation treatment strategies. <i>Clin Cancer Res; 21(17); 3969–76. ©2015 AACR</i>.</p></div>
Published Version (
Free)
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call