Abstract
To examine the relationship between cytotoxic T lymphocyte antigen 4 (CTLA-4) expression and breast cancer prognosis, CTLA-4 expression was immunohistochemically detected in paraffin-embedded specimens of primary tumors from 130 patients with breast cancer who had a mean follow-up period of 112 months. CTLA-4 expressed in cytoplasm of breast cancer cells and in cytoplasm and cell membranes of interstitial lymphocytes. Univariate analysis (log-rank) associated higher density of interstitial CTLA-4+ lymphocytes with longer DFS and OS, but higher tumor CTLA-4 expression with shorter OS. After controlling for age, clinical stage, Scarff-Bloom-Richardson grade, tumor thrombus, ER, PR, HER2 and Ki-67, multivariate analysis (Cox) showed that density of interstitial CTLA-4+ lymphocytes independently predicted longer DFS (HR 0.315, P = 0.002) and OS (HR 0.313, P = 0.005), whereas tumor CTLA-4 expression independently predicted shorter DFS (HR 2.176, P = 0.029) and OS (HR 2.820, P = 0.007), i.e., patients with high CTLA-4+ lymphocyte density and CTLA-4low tumor cells had the best prognoses. These results indicated that CTLA-4 expression in lymphocytes was associated with better prognosis, but that in tumor cells was associated with worse prognosis. Patients’ CTLA-4 profiles might thus be used to predict the benefits and toxicity of CTLA-4 blockade.Electronic supplementary materialThe online version of this article (doi:10.1007/s00262-015-1696-2) contains supplementary material, which is available to authorized users.
Highlights
Tumor-derived immune dysregulation is a key feature of breast cancer
overall survival (OS) (HR 2.820, P = 0.007), i.e., patients with high CTLA4+ lymphocyte density and CTLA-4low tumor cells had the best prognoses. These results indicated that cytotoxic T lymphocyte antigen 4 (CTLA-4) expression in lymphocytes was associated with better prognosis, but that in tumor cells was associated with worse prognosis
Multivariate analysis found that CTLA-4+ lymphocyte densityhigh was an independent predictor of longer Diseasefree survival (DFS) (HR 0.315, 95 % CL 0.150–0.658, P = 0.002) and OS (HR 0.313, 95 % CL 0.139–0.703, P = 0.005), whereas tumor CTLA-4high was an independent predictor of shorter DFS (HR 2.176, 95 % CL 1.084–4.437, P = 0.029) and OS (HR 2.820, 95 % CL 1.337–5.950, P = 0.007)
Summary
The immunosuppressive microenvironment derived from breast cancer cells consists of cytokines and immune checkpoint molecules that can block antitumor immunity [1,2,3]. CTLA-4 has much stronger binding affinity for the two ligands than CD28 [4]. CTLA-4 has three different isoforms: the full-length isoform with an extracellular ligand-binding domain and an intracellular signal-transducing domain; the soluble isoform that consists only of the extracellular domain; and the third isoform (which has only been identified in mice), which lacks the extracellular domain [5]
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