Abstract 4141: Role of interferon regulatory factor 5 in anti-tumor immunity: Orchestration of a functional tertiary lymphoid structure

The ability of breast cancer cells to metastasize is due to intrinsic intratumoral and extrinsic microenvironment changes. Many breast cancers are heavily infiltrated by immune cells and these infiltrating leukocytes are commonly observed around tumors in patients with invasive ductal carcinoma. Several recent studies show that the presence of tumor infiltrating leukocytes in human breast cancer tissue is associated with improved outcome, suggesting that the immune system is participating in the control and elimination of tumor cells. One way in which epithelial-derived cancers evade immunity is through dysregulation of cytokines and chemokines that “call in” specific immune cells to form a functional ectopic lymphoid-like structure termed a tertiary lymphoid structure (TLS) near the tumor. TLS are important for cell-mediated and humoral immunity and are extremely efficient immunological tools as the presentation of antigen occurs to both B and T cells. Although very little is known about the processes that drive TLS formation, data indicate that the presence of a TLS next to a solid cancer, including breast cancer, is a strong positive prognostic indicator. Recent data from our lab and others show that expression of the transcription factor interferon regulatory factor 5 (IRF5) in a human breast cancer molecular signature predicts increased survival and lower incidence of metastasis. We recently identified IRF5 as an important intrinsic regulator of mammary epithelial cell migration and metastasis. We also found that IRF5 within a breast tumor regulates the expression of cytokines/chemokines, such as CXCL13, that mediate immune cell trafficking. We previously reported that tumor-conditioned media (TCM) from IRF5-positive breast tumor cells contains CXCL13 and induces trafficking of CD19+CXCR5+ B cells and CD3+CD4+CXCR5+ T follicular helper-like (Tfh) cells to the TCM. CXCL13 is a key player in the formation of a TLS as it recruits in the specific cells and activates the B cells to produce immunoglobulins. Further analysis of immune cell trafficking to TCM from IRF5+ and IRF5- breast tumor cells reveals specificity for the trafficking of anti-tumorigenic B and T cell subsets to IRF5-positive TCM, such as transitional, memory, and plasmablast/plasma B cells, along with Th1 and Tfh cells, rather than pro-tumorigenic, immunosuppressive Bregs, Th2, and Tregs that were found to specifically migrate to IRF5-negative TCM. Analysis of formalin-fixed paraffin-embedded breast tumors by immunofluorescence microscopy revealed a significant correlation between IRF5 intratumoral expression and the presence of a TLS. Furthermore, preliminary data from a murine model of invasive mammary tumorigenesis supports a critical role for IRF5 in anti-tumor immunity. Together, these data implicate IRF5 in the generation of a functional TLS and as a critical mediator of anti-tumor immunity. Citation Format: Erica Pimenta, Ryan Weiss, Dan Li, Betsy Barnes. Role of interferon regulatory factor 5 in anti-tumor immunity: Orchestration of a functional tertiary lymphoid structure. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 4141.