P1-01-06: Mechanisms of Tumor Immune Escape in Triplenegative Breast Cancers (TNBC) with and without Mutated BRCA 1.

Abstract

Abstract Background Triplenegative breast cancer (TNBC) is associated with a dismal prognosis, although these tumors are chemosensitive. This phenomenon could be at least in part due to tumor immune escape. The current study investigates the host's immune response to TNBC cells and explores the presence of immunesuppressive factors, such as pAKT-expression and infiltration with FoxP3 positive regulatory T-cells (Tregs), in human TNBC samples. Material and Methods: NK-cell induced lysis of tumor cells was evaluated in human breast cancer cell lines MCF-7 (ER/PR pos.), HCC 1937 (triplenegative, BRCA 1 mutated) and HCC 1806 (triplenegative). Expression of pAKT and infiltration with Tregs was determined by immunehistochemistry and evaluated semiquantatitavely (0 no expression- 3 strong expression). Control groups consisted of: Fibroadenoma (N=6), prohpyhlactic mastectomy (BRCA 1 mutated, N=3), ER/PR + breast cancer (N=13). They were compared with triplenegative breast cancers: N = 9 BRCA wildtype and N = 6 BRCA 1 mutated. Results: At an effector target/target-ratio of 10/1 NK-cell induced lysis in HCC 1937 and HCC 1806 was 2.27 and 4.45 increased, respectively, as compared to MCF 7 cells. No infiltration with Tregs was detected in fibroadenoma and prophylactic mastectomy samples. Infiltration with FoxP3-positive Tregs was 0.92 +/− 0.75 in ER/PR+ breast cancers and 2.66 +/−0.5 (p<0.05) in TNBC and 2.16 +/−0.98 (p<0.05) in TNBC with BRCA mutation, respectively. Expression of pAKT was 1.45 +/− 1.29 in ER/PR + breast cancers and 1.77 +/−1.20 in TNBC and 2.66 +/−0.51 (p<0.05) TNBC/with BRCA mutation. Discussion: TNBC cells stimulated the NK-cell response to a stronger extent than did ER-positive MCF 7 cells mirrored by a more pronounced NK-cell- induced lysis. Thus, the observed stronger infiltration with FoxP3-positive Tregs in TNBC tumor samples could reflect a compensatory mechanism to suppress the host's immune response. In other tumor entities, such as ovarian cancer infiltration with Tregs is associated with a worse overall survival (1). Thus, the significantly increased infiltration with Tregs, could suggest that the worse prognosis of TNBC is due to tumor immune escape and further investigation of immunemodulatory therapeutic strategies in TNBC could prove fruitful. (1) Specific recruitment of regulatory T cells in ovarian carcinoma fosters immune privilege and predicts reduced survival. Curiel TJ, Coukos G, Zou L, Alvarez X, Cheng P, Mottram P, Evdemon-Hogan M, Conejo-Garcia JR, Zhang L, Burow M, Zhu Y, Wei S, Kryczek I, Daniel B, Gordon A, Myers L, Lackner A, Disis ML, Knutson KL, Chen L, Zou W. Nat Med. 2004 Sep;10(9):942–9. Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr P1-01-06.