Objective: We recently showed that tumors with an immunologically 'cold' phenotype are enriched for expression of stemness-associated genes and PVR/CD155, the ligand of the immunosuppressive molecule TIGIT. To explore the therapeutic implications of this finding, we investigated the relationship between PVR/CD155 expression, tumor-infiltrating lymphocytes (TIL), and prognosis in high-grade serous ovarian cancer (HGSC) and other cancers.
Methods: Expression of CD155, TIGIT, PD-1, PD-L1, and other immune markers in HGSC was assessed by high-dimensional flow cytometry, multi-color histological imaging, and/or gene expression profiling. The prognostic significance of PVR/CD155 and CD274/PD-L1 expression was assessed bioinformatically in HGSC and 32 other cancers in The Cancer Genome Atlas.
Results: T cells from HGSC frequently co-expressed TIGIT and PD-1, and the ratio of TIGIT to PD-1 expression increased markedly after in vitro expansion with a clinically relevant protocol. CD155 was commonly expressed on malignant epithelium in HGSC and showed a negative or non-significant association with TIL. In contrast, PD-L1 was predominantly expressed by tumor-associated macrophages and positively associated with TIL. These contrasts between CD155 and PD-L1 were seen across HGSC patients, across metastatic sites within individual patients, and even within individual tumor deposits. PVR/CD155 and CD274/PD-L1 exhibited divergent prognostic associations across diverse cancer types in TCGA, including HGSC.
Conclusions: CD155 and PD-L1 exhibit contrasting expression patterns, TIL associations and prognostic significance, suggesting they represent non-redundant immunosuppressive mechanisms. The CD155/TIGIT pathway represents a compelling immunotherapeutic target for HGSC and for immunologically cold tumors in general.
Keywords: CD155; Checkpoint blockade; Cold tumors; Immunotherapy; PD-L1; TIGIT.
Crown Copyright © 2020. Published by Elsevier Inc. All rights reserved.