Immunological Mechanisms in Breast Cancer - from Bench to Bedside

Abstract

technologies that could be used. Interestingly, one of the simplest approaches so far, the evaluation of TILs, has generated highly reproducible results on the relevance of immune parameters for response to neoadjuvant chemotherapy and patient prognosis, in particular in triple-negative breast cancer [9]. The evaluation of TILs can be performed using already existing H&E slides from histopathological diagnosis as well as slides collected in the course of clinical studies. The International Immunooncology Working Group (‘TIL Working Group’) has published a first guideline for the standardized evaluation of TILs [10], and the retrospective evaluation of a multitude of existing clinical trial cohorts for TIL levels is currently in progress. Furthermore, it is planned to use TILs as a stratification parameter in clinical trials on immunotherapeutic agents in breast cancer. In addition to the relatively simple evaluation of TILs, molecular signatures have been described that might offer additional predictive power [11], in particular in those tumors with intermediate and heterogeneous TIL levels. In addition to the primary diagnostic approaches, it will be important to monitor the development of resistance to immunotherapy. Over the last 20 years we have learned much about the interaction of solid tumors and the immune system. With this understanding has come a renaissance in cancer therapy, as immunotherapeutic interventions, which augment tumor-specific responses and block suppressive pathways on which tumors depend to maintain their immune privilege, have shown increasing efficacy in the clinic. However, despite the progress we have made in understanding these mechanisms we have just started to transfer this knowledge into therapeutic implications. Trastuzumab was the first antibody that could induce an antigen-specific antitumor immune reaction [12]. Until today it remains unclear whether the main effect of trastuzumab is related to immunological mechanisms or to synergistic activity with chemotherapy [13]. Meanwhile, many antibodies were approved for treating solid tumors including breast cancer. However, antibodies represent only a small component of the immunotherapeutic repertoire. Immunological parameters have been described as prognostic factors in many different tumor types, including colon cancer, malignant melanoma, and lung cancer, with promising results of clinical trials of immunomodulatory agents [1]. The upcoming immune therapies have the potential to transform the way malignant tumors are treated in many fields of oncology [2]. Traditionally, breast cancer has not been viewed as a particularly immunogenic type of tumor. Therefore, the first clinical trials of immune checkpoint inhibitors were focused on other types of tumors, such as malignant melanoma and non-small cell lung cancer. Nevertheless, immune parameters have been studied to a great extent in breast cancer [3] and accumulating data shows that they are relevant for the development and progression of this tumor type [4]. Consequently, immunotherapies of breast cancer are now tested in different clinical trials. In this issue of Breast Care the immunogenicity of breast cancer is described from various points of view. From the point of view of immunologists, the relevance of immune checkpoints is described in normal biological processes as well as malignant disease [5]. From the pathologist’s viewpoint, the analysis of tumor-infiltrating lymphocytes (TILs) offers a first approach to the correlation of different immunological patterns in breast cancer with therapy response, which can be further investigated by specific immunological markers [6]. From the viewpoint of the clinical oncologist, there is a variety of options to build therapeutic strategies on the increasing knowledge of the immunological mechanisms [7]. These new therapeutic options will – however – generate new challenges, for example in the field of molecular diagnostics [8]. In parallel to the new therapeutic approaches of immunotherapy, new diagnostic tests are needed. Not all patients will benefit from immunotherapy, and it will be essential to identify those patients that have the highest benefit as well as those patients that do not benefit from immunotherapy at all. From a diagnostic point of view, the immune system is particularly difficult to monitor, due to its high complexity and its high degree of spatial and temporal heterogeneity. There are different types of biomarkers as well as different Published online: April 27, 2016