Abstract PD7-08: Immune checkpoint upregulation and T-cell exhaustion in aggressive hormone-receptor positive breast cancer patients
Authors: Anurag M , Vasaikar S , Zhang X , Zhang B , Ellis MJ 
Published: May 2019

Background: Early reports from studies focused on assessing the clinical efficacy for immune-checkpoint (IC) inhibitors in breast cancer suggest lower activity than in cancers caused by exogenous mutagens such as melanoma and smoking-related lung cancer. Nonetheless, triple negative breast cancer is under active investigation. In contrast, estrogen receptor positive disease has been considered “immunologically silent” with very few IC studies focused on this disease subset. We therefore undertook an analysis of ER+ breast cancer to determine if there are subsets of patients with poor prognosis ER+ disease that exhibit IC pathway upregulation hence potential candidates for IC-based clinical trials.

Methods: In an unbiased integrative analysis of patient samples, mRNA expression data for ˜15500 genes across 66 Luminal B patient set was used to identify genes for which the expression correlated positively with proliferation marker Ki67 (in aromatase-inhibitor treated tumors) and were upregulated (&gt;2 fold) in endocrine-therapy (ET) resistant samples as compared against the sensitive counterparts. Resulting genes were queried to identify underlying activated pathways and prioritize genes for further analysis. Validation of shortlisted genes was performed on independent patient cohorts (TCGA and METABRIC) using Kaplain-Meier disease-specific survival analysis. Amplification and methylation data for TCGA samples were obtained from CBioportal and Wanderer respectively. Proteomics data for TCGA samples was extracted using LikedOmics server. T-cell activation (TCA) and exhaustion (TCE) scores were devised using mean of standardized expression of genes reported to contribute in these two T cell states.

Result: Approximately 30 genes were found to be deferentially upregulated in ET-resistant aggressive ER+ breast cancer. This gene set was enriched in immune-tolerance biological processes (p&lt;0.005). The three immune-checkpoints constituting these processes are IDO1, LAG3 and PDCD1 (PD1). Upregulation of IDO1 was a confirmed poor prognosis factor across independent patient cohorts. Furthermore, comparative analysis of TCA and TCE scores between ET-resistant and sensitive tumors revealed that resistant tumors have high TCE, despite having high TCA, hence circumventing immunogenic apoptosis.

Conclusion: To date, no substantial study showing prognostic relevance of mRNA levels of ICs in context of ER+ breast cancer patients has been reported. Higher IDO1 and T-cell exhaustion levels in ET-resistant ER+ disease provides clinical evidence for a role for immune-checkpoints in evading immune-driven cell death. These results suggest a potential for IC targeted immunotherapy for ˜ 80% of endocrine therapy resistant clinically aggressive ER+ breast cancers.

Citation Format: Anurag M, Vasaikar S, Zhang X, Zhang B, Ellis MJ. Immune checkpoint upregulation and T-cell exhaustion in aggressive hormone-receptor positive breast cancer patients [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr PD7-08.