title: Restoring Lost Anti-HER-2 Th1 Immunity in Breast Cancer: A Crucial Role for Th1 Cytokines in Therapy and Prevention.
abstract: The ErbB/B2 (HER-2/neu) oncogene family plays a critical role in the development and metastatic spread of several tumor types including breast, ovarian and gastric cancer. In breast cancer, HER-2/neu is expressed in early disease development in a large percentage of DCIS lesions and its expression is associated with an increased risk of invasion and recurrence. Targeting HER-2 with antibodies such as trastuzumab or pertuzumab has improved survival, but patients with more extensive disease may develop resistance to therapy. Interestingly, response to HER-2 targeted therapies correlates with presence of immune response genes in the breast. Th1 cell production of the cytokines interferon gamma (IFNγ) and TNFα can enhance MHC class I expression, PD-L1 expression, augment apoptosis and tumor senescence, and enhances growth inhibition of many anti-breast cancer agents, including anti-estrogens and HER-2 targeted therapies. Recently, we have identified that a loss of anti-HER-2 CD4 Th1 in peripheral blood occurs during breast tumorigenesis and is dramatically diminished, even in Stage I breast cancers. The loss of anti-HER-2 Th1 response is specific and not readily reversed by standard therapies. In fact, this loss of anti-HER-2 Th1 response in peripheral blood correlates with lack of complete response to neoadjuvant therapy and diminished disease-free survival. This defect can be restored with HER-2 vaccinations in both DCIS and IBC. Correcting the anti-HER-2 Th1 response may have significant impact in improving response to HER-2 targeted therapies. Development of immune monitoring systems for anti-HER-2 Th1 to identify patients at risk for recurrence could be critical to improving outcomes, since the anti-HER-2 Th1 response can be restored by vaccination. Correction of the cellular immune response against HER-2 may prevent recurrence in high-risk patients with DCIS and IBC at risk of developing new or recurrent breast cancer.
authors.affiliation: Department of Surgery, University of Pennsylvania Perelman School of Medicine Philadelphia, PA, USA.
authors.forename: Nadia F
authors.initials: NF
authors.lastname: Nocera
authors.affiliation: Comprehensive Breast Program, H. Lee Moffitt Cancer Center Tampa, FL, USA.
authors.forename: M Catherine
authors.initials: MC
authors.lastname: Lee
authors.affiliation: Department of Surgery, University of Pennsylvania Perelman School of Medicine Philadelphia, PA, USA.
authors.forename: Lucy M
authors.initials: LM
authors.lastname: De La Cruz
authors.affiliation: Department of Surgery, University of Pennsylvania Perelman School of Medicine Philadelphia, PA, USA.
authors.forename: Cinthia
authors.initials: C
authors.lastname: Rosemblit
authors.affiliation: Comprehensive Breast Program, H. Lee Moffitt Cancer Center Tampa, FL, USA.
authors.forename: Brian J
authors.initials: BJ
authors.lastname: Czerniecki
keywords: HER2; Th1 immunity; breast cancer; cancer vaccines; immunotherapy