Background: Targeting programmed cell death receptor l pathway (anti-PD-1/PD-L1) demonstrated objective clinical response rates in a subgroup of patients with metastatic breast cancer with overall response rates of up to 20%. However, the vast majority of breast cancer patients is not responding to immune checkpoint blockade. With regard to the diverse tumor biology of breast cancer and recent data, immune evasion is likely mediated by various, coincident mechanisms. Consequently, our objective was to identify patterns of immune responses during the transition of primary to metastatic breast cancer.

Methods: We performed comprehensive immunohistochemistry on both tumor and immune cells in two independent, matched cohorts of 67 primary and metastatic breast cancer patients. Further, the analysis was integrated with mRNA expression levels (RT-qPCR) of key regulatory and effector function immune genes and clinical as well as histopathologic parameters.

Results: Both, immunohistochemistry and mRNA gene expression profiling of immune genes revealed immunological ignorance, defined as an immunological “cold” tumor by particularly low infiltration of CD8+ T cells and corresponding immune gene and effector function, as a key feature of primary to metastatic breast cancer transition. However, CD8+ T cell infiltration and effector function (Granzyme B, Interferon-γ) where found to be an independent prognostic marker for PFS and OS. Unsupervised hierarchical clustering and regression analysis identified distinct immune response types according to T-cell infiltration, interferon-γ signalling (IFNG), immunosuppression (IDO, TGF-β, FOXP3) and humoral immune responses (Immunoglobulin κ constant; IGKC). Expression of programmed death receptor 1 ligand (PD-L1), and T-cell immunoglobulin and mucin-domain containing-3 (TIM-3) where linked to CD8+ T cells and associated with a better prognosis only in triple negative breast cancer patients. Importantly, induction of CD4+ and CD8+ T cell infiltration as well as humoral immune responses (IGKC, CXCL13) in matched pairs during progression from primary to metastatic disease, where strongly associated with improved distant disease free and overall survival.

Conclusion: Our findings demonstrate a switch to a less immunoreactive environment in metastatic compared to matched, primary samples of breast cancer patients. Nevertheless, induction of T-cell mediated immunity during tumor evolution, observed across all biologic subtypes, warrants further research with the overall goal to convert immunologically ignorant breast cancers and to stratify future immunotherapies.

Citation Format: Fremd C, Halama N, Wirtz R, Zoernig I, Sinn H-P, Varga Z, Feisst M, Deutsch T, Schuetz F, Schneeweiss A, Jaeger D, Wallwiener M. Immune related gene expression to explore immue escape in primary to metastatic breast cancer transition [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 P4-06-10.