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.

Crosstalk between HER2 and PD-1/PD-L1 in Breast Cancer: From Clinical Applications to Mathematical Models

“…As mentioned in [102,117,127] the experimental analysis on HER2 + patients suggests that CD8 + T cell-mediated cytotoxicity and PD-L1 expression together may predict improved outcome in HER2 + BC patients under combined chemotherapy and HER2-targeted therapy [102]. These findings emphasize the importance of tumor-immune interaction in BC progression [46,73,114,128,129]. Moreover, based on 6 different studies, in [130], the authors highlight that PD-L1 expression in both tumor cells and immune cells of the host can contribute to the overall response to treatment.…”

The Intriguing History of Cancer Immunotherapy

“…Other autologous cancer vaccines are being studied in numerous laboratories all over the world including University of Pennsylvania researchers who are testing an experimental breast cancer vaccine (21,76). It is widely accepted that HER-2/neu (ErbB) oncogene family plays an important role in growth, development and metastasis of several tumor types including ovarian and breast cancer (77). HER-2/neu (ErbB) was found to be expressed very early in the breast cancer development and the expression of this gene was associated with a significantly increased risk of cancer recurrence after treatment (77).…”

“…It is widely accepted that HER-2/neu (ErbB) oncogene family plays an important role in growth, development and metastasis of several tumor types including ovarian and breast cancer (77). HER-2/neu (ErbB) was found to be expressed very early in the breast cancer development and the expression of this gene was associated with a significantly increased risk of cancer recurrence after treatment (77). The hope is that the anti-HER-2 response provided by the lab-manipulated Th1 immune cells can be successfully restored by a cancer vaccine (77).…”

“…HER-2/neu (ErbB) was found to be expressed very early in the breast cancer development and the expression of this gene was associated with a significantly increased risk of cancer recurrence after treatment (77). The hope is that the anti-HER-2 response provided by the lab-manipulated Th1 immune cells can be successfully restored by a cancer vaccine (77).…”

Screening of Human Epidermal Growth Factor Receptor 2 (HER2) Extracellular Domain for Potential Epitopes by Using Immuno-informatics Tools.

“…Cancer immunotherapy does include different modalities like vaccination, adoptive T-cells therapy and chimeric antigen receptor (CAR) T-cells therapy [3]. These forms of immunotherapy are designed to enhance the capacity of tumor in ltrating lymphocytes (TILs) to recognize tumor associated antigen (TAA) and hence halt tumor progression [4].…”