The Role of the Tumor Microenvironment in Developing Successful Therapeutic and Secondary Prophylactic Breast Cancer Vaccines

Abstract

Breast cancer affects roughly one in eight women over their lifetime and is a leading cause of cancer-related death in women. While outcomes have improved in recent years, prognosis remains poor for patients who present with either disseminated disease or aggressive molecular subtypes. Cancer immunotherapy has revolutionized the treatment of several cancers, with therapeutic vaccines aiming to direct the cytotoxic immune program against tumor cells showing particular promise. However, these results have yet to translate to breast cancer, which remains largely refractory from such approaches. Recent evidence suggests that the breast tumor microenvironment (TME) is an important and long understudied barrier to the efficacy of therapeutic vaccines. Through an improved understanding of the complex and biologically diverse breast TME, it may be possible to advance new combination strategies to render breast carcinomas sensitive to the effects of therapeutic vaccines. Here, we discuss past and present efforts to advance therapeutic vaccines in the treatment of breast cancer, the molecular mechanisms through which the TME contributes to the failure of such approaches, as well as the potential means through which these can be overcome.

High expression of DLL3 is associated with a poor prognosis and immune infiltration in invasive breast cancer patients

“…The proportion of immune cells in the TME plays an important role in tumor cell survival and tumor patient prognosis [ [35] , [36] – 37 ]. In our study, a noteworthy conclusion was that the expression of DLL3 is associated with the level of immune infiltration in IBC.…”

Vaccination against Her-2/neu, with focus on peptide-based vaccines

“…The breast tumor microenvironment (TME) has been shown to be an important and a long understudied barrier to the efficacy of therapeutic vaccines. 103 Therefore, combination strategies are being evaluated to add additional strategies for modulating the TME and killing the tumor cells, for example, by combining a tumor-specific cancer vaccine with immune checkpoint inhibitors. 76 , 104 , 105 , 106 , 107 Our group has taken this concept of combination therapy one step forward and has recently identified the mimotope of the immune checkpoint PD-1 and has shown the enhanced anti-tumor effect of HER-Vaxx in combination with this mimotope 76 , 107 ; along this line, the combination of a PD-1 peptide (PD1-Vaxx) and B-Vaxx is planned to be evaluated in a clinical trial.…”

Recent Progress on Therapeutic Vaccines for Breast Cancer

“…In addition to TAAs and TSAs, multiple TME-targeting vaccine-based clinical trials are underway for patients with BC ( 38 ). Resident cells in the TME are likely more genomically stable than tumor cells.…”