Abstract 483: TIGIT/PVR/NECTIN immune checkpoint axis expression across breast cancer subtypes
Authors: DuPree Kelly J. , Molinero Luciana 
Published: July 2021

Abstract
Background: Targeting the PD1:PD-L1 pathway revolutionized treatment options for patients with metastatic triple negative breast cancer (TNBC). Other immune checkpoint inhibitors are being investigated in clinical settings, such as anti-TIGIT antibodies. The goal of this analysis was to evaluate the expression of the TIGIT/PVR/NECTIN molecule family in breast cancer subtypes.
Methods: We used the publicly available METABRIC dataset (Curtis C, Nature 2012; Pereira B, Nature Comm 2016) to evaluate microarray RNA expression levels for TIGIT, CD226, PVR, PVRIG, NECTIN2, NECTIN3, NECTIN4, PDCD1 and CD274 from primary breast tumors annotated with ER, PR and HER2 IHC status (Hormone receptor positive [HR+]: n=1369; HER2 amplified [HER2+]: n=236; TNBC: n=299). Biomarker association with overall survival (OS) was evaluated using Cox proportional hazard analysis adjusted for clinical covariates.
Results: Expression of the TIGIT/PVR/NECTIN members revealed three expression patterns across breast cancer subtypes: 1) highest in TNBC, followed by HER2+ and then by HR+ BC (PVR); 2) similar levels in TNBC and HER2+, and higher than HR+ BC (TIGIT, CD226, PVRIG, NECTIN4); 3) highest in HR+, followed by HER2+ and then by TNBC (NECTIN2). NECTIN3 showed the lowest expression differences across subtypes. Correlation of these genes with each other varied: 1) Receptors TIGIT, CD226 and PVRIG were moderately correlated with each other and with PDCD1 (Pearson correlation index [r]: 0.45 - 0.78) and strongly correlated with the T cell markers CD3E, CD8A, and GZMB (r: 0.53 - 0.90); 2) PVR family ligands PVR, NECTIN2, NECTIN3 and NECTIN4 were not correlated with each other, nor to the receptors or biomarkers for T-cell, macrophage or stromal biology (r: -0.36 - 0.30). CD274, the PD1 ligand, was weakly associated with TIGIT, CD226, PVRIG, PDCD1 and with immune cell markers (0.25 - 0.38). This pattern was similar across breast cancer subtypes. No OS prognostic value was observed for the TIGIT/PVR family members in HR+ or HER2+ BC. Only CD226 was associated with an improved OS in TNBC (HR: 0.69 [0.48-0.99]). As expected, PDCD1, CD274, and T-cell biomarkers were linked to improved OS prognosis (HR: 0.61-0.69), observed only in TNBC.
Conclusions: Overall, RNA expression levels of TIGIT/PVR/NECTIN family members are higher in HER2+ and TNBC compared to HR+ in the large breast cancer METABRIC dataset. While TIGIT, CD226 and PVRIG are clearly associated with T cells, the cell subsets expressing the PVR/NECTIN ligands remain to be defined in breast cancer. Our analysis suggests that TNBC and HER2+ are the breast cancer subtypes more likely to benefit from anti-TIGIT therapeutic targeting.
Citation Format: Kelly J. DuPree, Luciana Molinero. TIGIT/PVR/NECTIN immune checkpoint axis expression across breast cancer subtypes [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 483.