Breast cancer instructs dendritic cells to express OX40 ligand and to prime pro-inflammatory type 2 CD4+ T cells that facilitate tumor development.

CTRC-AACR San Antonio Breast Cancer Symposium: 2008 Abstracts Abstract #1050 We found that breast cancer tumors are infiltrated with mature dendritic cells (DCs), which cluster with CD4+ T cells. CD4+ T cells infiltrating breast cancer tumors secrete type 1 (IFN-g), pro-inflammatory (TNF) as well as high levels of type 2 (IL-4 and IL-13) cytokines. Immunofluorescence staining of tissue sections revealed intense IL-13 staining on breast cancer cells. The expression of phosphorylated STAT6 in breast cancer cells suggests that IL-13 actually delivers signals to cancer cells. To determine the link between breast cancer, DCs and CD4+ T cells, we implanted human breast cancer cell lines in NOD/SCID b2m-/- mice engrafted with human CD34+ hematopoietic progenitor cells (HPCs) and autologous T cells. There, CD4+ T cells promote early tumor development. This can be prevented by administration of IL-13 antagonists and is dependent on DCs. Furthermore, these humanized mice demonstrate a signature of IL-13. Similarly to patient samples, in humanized mice breast cancer but not melanoma tumors are infiltrated with large numbers of human myeloid DCs. DC isolated from breast tumor and its draining lymph nodes induce the production of high level of IL4, IL13 and TNF by naive CD4 T cells further demonstrating that breast tumor modulates DC to induce an inflammatory Th2 response. Accordingly, immunofluorescence staining of breast cancer tissue sections from patients shows high expression of OX40 ligand on DCs. This can be ascribed to activity of breast cancer cell-derived soluble factors. Finally, blocking OX40 ligand prevents generation of IL-13 secreting CD4+ T cells. Thus, breast cancer targets DCs to generate pro-inflammatory type 2 immunity that promotes its development. Supported by U19 [AIO57234][1], RO-1 CA89440, CA78846, and CA85540. Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr 1050. [1]: /lookup/external-ref?link_type=GENPEPT&access_num=AIO57234&atom=%2Fcanres%2F69%2F2_Supplement%2F1050.atom