Abstract
<div>AbstractPurpose:<p>In multiple oncological settings, expression of the coinhibitory ligand PD-L1 by malignant cells and tumor infiltration by immune cells expressing coinhibitory receptors such as PD-1, CTLA4, LAG-3, or TIM-3 conveys prognostic or predictive information. Conversely, the impact of these features of the tumor microenvironment on disease outcome among high-grade serous carcinoma (HGSC) patients remains controversial.</p>Experimental Design:<p>We harnessed a retrospective cohort of 80 chemotherapy-naïve HGSC patients to investigate PD-L1 expression and tumor infiltration by CD8<sup>+</sup> T cells, CD20<sup>+</sup> B cells, DC-LAMP<sup>+</sup> dendritic cells as well as by PD-1<sup>+</sup>, CTLA4<sup>+</sup>, LAG-3<sup>+</sup>, and TIM-3<sup>+</sup> cells in relation with prognosis and function orientation of the tumor microenvironment. IHC data were complemented with transcriptomic and functional studies on a second prospective cohort of freshly resected HGSC samples. <i>In silico</i> analysis of publicly available RNA expression data from 308 HGSC samples was used as a confirmatory approach.</p>Results:<p>High levels of PD-L1 and high densities of PD-1<sup>+</sup> cells in the microenvironment of HGSCs were strongly associated with an immune contexture characterized by a robust T<sub>H</sub>1 polarization and cytotoxic orientation that enabled superior clinical benefits. Moreover, PD-1<sup>+</sup>TIM-3<sup>+</sup>CD8<sup>+</sup> T cells presented all features of functional exhaustion and correlated with poor disease outcome. However, although PD-L1 levels and tumor infiltration by TIM-3<sup>+</sup> cells improved patient stratification based on the intratumoral abundance of CD8<sup>+</sup> T cells, the amount of PD-1<sup>+</sup> cells failed to do so.</p>Conclusions:<p>Our data indicate that PD-L1 and TIM-3 constitute prognostically relevant biomarkers of active and suppressed immune responses against HGSC, respectively.</p></div>
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