TGFβ can play an important role in tumor progression. Whether expressed by the tumor, or the tumor microenvironment, it has a profound impact on not only the tumor itself but also the host immune system. There are three isoforms of TGFβ: TGFβ1, TGFβ2 and TGFβ3. The functions of TGFβ1 and 2 have been widely studied. However, little is known about how TGFβ3 affects both tumor growth and the host. Here we used a novel human antibody that neutralizes only TGFβ1 and 2, while leaving TGFβ3 activity untouched. By specifically blocking TGFβ1 and 2 functions, we were able to investigate the role of TGFβ3 in modulating the immune compartment, and its ability to combat tumor growth. We used the 4T1 murine breast carcinoma model, which secretes all three isoforms of TGFβ. Tumor-bearing mice were treated with 10mg/kg the novel anti-TGFβ1/2 antibody, which inhibited 25% of 4T1 tumor growth after 20 days. We evaluated the immune cells from tumors and found there was a significant increase (14%) in the NK cells that infiltrated the tumor site in the antibody-treated group. To explore the mechanism underlying this phenomenon, we evaluated the effect of tumor-secreted TGFβ isoforms on NK cells in vitro in a co-culture system. When 4T1 tumor cells were co-cultured with enriched NK cells, the TGFβ1/2 antibody elevated the levels of IFNγ, GzmB and perforin. However, the expression levels of NKG2D, CD69, Ly49A and C were unchanged. We also detected a significant upregulation of FasL on NK cells treated with the TGFβ1/2 antibody. Moreover, NK cells treated with the TGFβ1/2 antibody in the co-culture system showed improved killing activity towards Yac-1 cells, which was confirmed to be mediated by GzmB. In summary, a novel therapeutic antibody candidate that specifically neutralizes TGFβ1 and 2 inhibits 4T1 tumor growth by (i) changing the tumor microenvironment to attract NK cells to tumor sites; and (ii) by increasing NK cell function via upregulation of FasL and GzmB.
Citation Format: Ou Li, Shireen Khan, Nerissa Mendoza, Sandra Vanegas, Cat Tran, Amer Mirza. A novel TGFβ 1/2 specific antibody suppresses 4T1 tumor growth by enhancing NK cell recruitment and function. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr LB-151. doi:10.1158/1538-7445.AM2014-LB-151